Aromatic sulfone hydroxamic acid metalloprotease inhibitor

ABSTRACT

A treatment process is disclosed that comprises administering an effective amount of an aromatic sulfone hydroxamic acid that exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1 to a host having a condition associated with pathological matrix metalloprotease activity. Also disclosed are metalloprotease inhibitor compounds having those selective activities, processes for manufacture of such compounds and pharmaceutical compositions using an inhibitor. A contemplated compound corresponds in structure to formula B, below,

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This is a continuation-in-part of application Ser. No. 09/311,837 filed on May 14, 1999 that was a continuation-in-part of application Ser. No. 09/256,948 filed on Feb. 24, 1999, that was a continuation-in-part of application Ser. No. 09/74497 filed on Nov. 13, 1998.

TECHNICAL FIELD

[0002] This invention is directed to proteinase (protease) inhibitors, and more particularly to the use of aromatic sulfone hydroxamic acid compounds that, inter alia, are selective inhibitors of matrix metalloproteinases in a process for treating conditions associated with pathological matrix metalloproteinase activity, the selective inhibitors themselves, compositions of proteinase inhibitors, intermediates for the syntheses of proteinase inhibitors, and processes for the preparation of proteinase inhibitors.

BACKGROUND OF THE INVENTION

[0003] Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. Th se biochemicals makeup, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.

[0004] Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason leads to a number of disease states. Inhibition of the enzymes responsible loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.

[0005] Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases).

[0006] The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.

[0007] The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimers Disease; coronary thrombosis and bone disease. Defective injury repair processes also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.

[0008] Metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF), and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-α, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal, and TNF can help control the growth of tumor cells.

[0009] TNF-α convertase is a metalloprotease involved in the formation of soluble TNF-α. Inhibition of TNF-α convertase (TACE) inhibits production of active TNF-α. Compounds that inhibit both MMPs activity and TNF-α production have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1994)). There remains a need for effective MMP inhibitors. There also remains a need for effective TNF-α convertase inhibiting agents.

[0010] MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (β-Amyloid Precursor Protein) to the amyloid plaque and inactivation of α₁-protease inhibitor (α₁-PI). Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as α₁-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.

[0011] Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin, gelatinase A or B, or collagenase III appear to be the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile. Osteoarthritis, another prevalent disease wherein it is believed that cartilage degradation of inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).

[0012] Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitors of metalloproteinases (TIMPs), α₂-macroglobulin and their analogs or derivatives. These endogenous inhibitors are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure.

[0013] Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, WO95/12389, WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMP inhibitors are disclosed in a number of published patent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones, as does the article by Schwartz et al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. New Drugs, 15(3): 175-185 (1997).

[0014] One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes. For example, the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC₅₀ values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC₅₀ value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).

[0015] Meta analysis of data from Phase I/II studies using marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted. The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction permits treatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.

[0016] International application WO 98/38163, published on Sep. 3, 1998 disclose a large group of hydroxamate inhibitors of MMPs and TACE. The compounds of WO 98/38163 contain one or two substituents adjacent to the hydroxamate functionality and a substituent that can be an aromatic sulfonyl group adjacent to those one or two substituents.

[0017] International application WO 98/37877, published on Sep. 3, 1998 discloses compounds that contain a 5- to 7-membered heterocyclic ring adjacent to the hydroxamate functionality and can contain an aromatic sulfonyl group adjacent to the heterocyclic ring.

[0018] Although many of the known MMP inhibitors such as batimastat, marimastat and the hydroxamates of WO 98/37877 and WO 98/38163 exhibit a broad spectrum of activity against MMPS, those compounds are not particularly selective in their inhibitory activity. This lack of selectivity may be the cause of the musculoskeletal pain and stiffness observed with their use. In addition, it can be therapeutically advantageous to utilize a medicament that is selective in its activity as compared to a generally active material so that treatment can be more closely tailored to the pathological condition presented by the host mammal. The disclosure that follows describes a process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that utilizes a compound that selectively inhibits one or more MMPs, while exhibiting less activity against at least MMP-1.

SUMMARY OF THE INVENTION

[0019] The present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. A contemplated molecule, inter alia, exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1. By “substantially less” it is meant that a contemplated compound exhibits an IC₅₀ value ratio against one or more of MMP-2, MMP-9 or MMP-13 as compared to its IC₅₀ value against MMP-1, e.g., IC₅₀ MMP-2:IC₅₀ MMP-1, that is less than about 1:10, preferably less than about 1:100, and most preferably less than about 1:1000 in the in vitro inhibition assay utilized hereinafter. The invention also contemplates particular compounds that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1, as well as a composition containing such a MMP inhibitor as active ingredient. Similarly contemplated are particular compounds such as those of Examples 16, 498, 667, 672 and 684 that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-7, as well as a composition containing such a MMP inhibitor as active ingredient. The invention further contemplates intermediates in the preparation of a contemplated aromatic sulfone hydroxamic acid molecule and a process for preparing an aromatic sulfone hydroxamic acid molecule.

[0020] Briefly, one embodiment of the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor that selectively inhibits matrix metalloprotease activity as above in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. The administered enzyme inhibitor corresponds in structure to formula I, below, or a pharmaceutically acceptable salt thereof:

[0021] wherein

[0022] R¹ and R² are both hydrido or R¹ and R² together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring that are oxygen, sulfur or nitrogen.

[0023] R³ in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical. When R³ is a substituted aryl or heteroaryl radical, a contemplated substituent is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxy, arylthio, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic.

[0024] The substituent bonded to the aryl or heteroaryl radical of which the R³ radical is comprised itself can be substituted with one or more substituents; i.e., the substituting substituent is optionally substituted. When that aryl or heteroaryl radical is substituted, and the substituting moiety (group, substituent, or radical) is itself substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,

[0025] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino

[0026] wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group,

[0027] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group

[0028] wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.

[0029] Preferably, the R³ substituent is Ph-Q-A-R-E-Y wherein Ph is phenyl substituted at the 4-position relative to the depicted SO₂ group, and -Q-A-R-E-Y is a substituent in which Q is a 5- to 7-membered heterocyclic ring containing one or two nitrogen atoms, one of which is bonded the depicted phenyl group, and whose remaining members are defined hereinafter for the substituent G-A-R-E-Y.

[0030] A compound of formula I is a compound of more general formula A, wherein R³, R¹ and R² are as defined before and R²⁰ is defined below.

[0031] The substituent R²⁰ is (a) —O—R²¹, where R²¹ is selected from the group consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group and a pharmaceutically acceptable cation, (b) —NH—O—R²² wherein R²² is a selectively removable protecting group such as a 2-tetrahydropyranyl., benzyl, p-methoxybenzyl (MOZ), carbonyl-C₁-C₆-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C₁-C₆-alkyl, aryl, or ar-C₁-C₆-alkyl or a mixture thereof, (c) —NH—O—R¹⁴, where R¹⁴ is hydrido, a pharmaceutically acceptable cation or C(W)R²⁵ where W is O (oxo) or S (thioxo) and R²⁵ is selected from the group consisting of an C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, ar-C₁-C₆-alkoxy, ar-C₁-C₆-alkyl, heteroaryl and amino C₁-C₆-alkyl group wherein the amino C₁-C₆-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ar-C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxycarbonyl, and C₁-C₆-alkanoyl radical, or (iii) wherein the amino C₁-C₆-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR²⁶R²⁷, where R²⁶ and R²⁷ are independently selected from the group consisting of a hydrido, C₁-C₆-alkyl, amino C₁-C₆-alkyl, hydroxy C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group, or R²⁶ and R²⁷ together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur. When used in a contemplated process or method, R²⁰ is —NH—O—R²², as defined above.

[0032] In preferred practice, R¹ and R² together with the atoms to which they are bonded form a 6-membered ring.

[0033] An R³ radical preferably has a length that is greater than that of a pentyl group [a —(CH₂)₄CH₃ chain], more preferably greater than about that of a hexyl group [a —(CH₂)₅CH₃ chain], and most preferably greater than an octyl group [a —(CH₂)₇CH₃ chain]. An R³ radical preferably has a length that is less than that of an icosyl group [a —(CH₂)₁₉CH₃ chain], and more preferably a length that is less than that of a stearyl group [a —(CH₂)₁₇CH₃ chain). A preferred R³ group contains two or more 5- or 6-membered rings. A contemplated R³ group, when rotated about an axis drawn through the SO₂-bonded 1-position and the substituent-bonded 4-position of a 6-membered ring or the SO₂-bonded 1-position and substituent-bonded 3- or 4-position of a 5-membered ring, defines a three-dimensional volume whose widest dimension has the width in a direction transverse to that axis to rotation of about one furanyl ring to about two phenyl rings.

[0034] It is also preferred that a R³ radical be a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring or at its own 3- or 4-position when a 5-membered ring with an optionally substituted substituent selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C₃-C₁₄ alkyl group, a N-piperidyl group, a N-piperazyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group and a benzamido group. The substituent of the 5- or 6-membered aryl or heteroaryl group can itself be substituted as discussed before.

[0035] A preferred compound for use in a contemplated process has a structure that corresponds to formula II, below, or a pharmaceutically acceptable salt thereof:

[0036] wherein

[0037] R¹⁴ is hydrido, a pharmaceutically acceptable cation or C(W)R¹⁵ where W is O or S and R¹⁵ is selected from the group consisting of an C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, ar-C₁-C₆-alkoxy, ar-C₁-C₆-alkyl, heteroaryl and amino C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ar-C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxycarbonyl, and C₁-C₆-alkanoyl radical, or (iii) wherein the amino C₁-C₆-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;

[0038] m is zero, 1 or 2;

[0039] n is zero, 1 or 2;

[0040] p is zero, 1 or 2;

[0041] the sum of m+n+p=1, 2, 3 or 4;

[0042] (a) one of X, Y and Z is selected from the group consisting of C(O), NR⁶, O, S, S(O), S(O)₂ and NS(O)₂R⁷, and the remaining two of X, Y and Z are CR⁸R⁹, and CR¹⁰R¹¹, or

[0043] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR⁶C(O), NR⁶S(O), NR⁶S(O)₂, NR⁶S, NR⁶O, SS, NR⁶NR⁶ and OC(O), with the remaining one of X, Y and Z being CR⁸R⁹, or

[0044] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of

[0045] wherein wavy lines are bonds to the atoms of the depicted ring;

[0046] R⁶ and R⁶′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkylcarbonyl, hydroxycarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C₁-C₆-alkylcarbonylcarbonyl, R⁸R⁹-aminocarbonylcarbonyl, C₁-C₆-alkanoyl, aryl-C₁-C₆-alkyl, aroyl, bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)-C₁-C₆-alkyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-perfluoroalkyl, C₁-C₆-trifluoromethylalkyl, C₁-C₆-perfluoroalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C₃-C₈-heterocycloalkyl, C₃-C₈-heterocycloalkylcarbonyl, aryl, C₅-C₆-heterocyclo, C₅-C₆-heteroaryl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, arylsulfonyl, C₁-C₆-alkylsulfonyl, Cs-C₆-heteroarylsulfonyl, carboxy-C₁-C₆-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl, aminocarbonyl, C₁-C₆-alkyl(R⁸N)iminocarbonyl, aryl(R⁸N)iminocarbonyl, C₅-C₆-heterocyclo(R⁸N)iminocarbonyl, arylthio-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₃-C₆-alkenyl, C₁-C₄-alkylthio-C₃-C₆-alkenyl, C₅-C₆-heteroaryl-C₁-C₆-alkyl, halo-C₁-C₆-alkanoyl, hydroxy-C₁-C₆-alkanoyl, thiol-C₁-C₆-alkanoyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkoxycarbonyl, aryloxycarbonyl, NR⁸R⁹—(R⁸)iminomethyl, NR⁸R⁹—C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, R⁸R⁹-aminocarbonyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkylcarbonyl, hydroxyaminocarbonyl, R⁸R⁹-aminosulfonyl, R⁸R⁹-aminosulfon-C₁-C₆-alkyl, R⁸R⁹-amino-C₁-C₆-alkylsulfonyl and an R⁸R⁹-amino-C₁-C₆-alkyl group;

[0047] R⁷ is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl and a C₁-C₆-hydroxyalkyl group;

[0048] R⁸ and R⁹ and R¹⁰ and R¹¹ are independently selected from the group consisting of a hydrido, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, ar-C₁-C₆-alkyl, heteroaryl, heteroar-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thio]-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, aralkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl and C₁-C₆-alkanoyl, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹ and the carbon to which they are bonded form a carbonyl group, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹, or R⁸ and R¹⁰ together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R⁸ and R⁹ or R¹⁰ and R¹¹ is hydroxy;

[0049] R¹² and R¹²′ are independently selected from the group consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, heteroaryl, heteroaralkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl and C₁-C₆-alkanoyl;

[0050] R¹³ is selected from the group consisting of a hydrido, benzyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl and a C₁-C₆-hydroxyalkyl group; and

[0051] G-A-R-E-Y is a substituent that preferably has a length greater than that of a pentyl group, and more preferably has a length greater than that of a hexyl group. The substituent G-A-R-E-Y preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent:

[0052] G is an aryl or heteroaryl group;

[0053] A is selected from the group consisting of

[0054] (1) —O—;

[0055] (2) —S—;

[0056] (3) —NR¹⁷—;

[0057] (4) —CO—N(R¹⁷) or —N(R¹⁷)—CO—, wherein R¹⁷ is hydrogen, C₁-C₄-alkyl, or phenyl;

[0058] (5) —CO—O— or —O—CO—;

[0059] (6) —O—CO—O—;

[0060] (7) —HC═CH—;

[0061] (8) —NH—CO—NH—;

[0062] (9) —C≡C—;

[0063] (10) —NH—CO—O— or —O—CO—NH—;

[0064] (11) —N═N—;

[0065] (12) —NH—NH—; and

[0066] (13) —CS—N(R¹⁸)— or —N(R¹⁸)—CS—, wherein

[0067] R¹⁸ is hydrogen C₁-C₄-alkyl, or phenyl; or

[0068] (14) A is absent and G is bonded directly to R;

[0069] R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C₁-C₂-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group, and R is other than alkyl or alkoxyalkyl when A is —O— or —S—;

[0070] E is selected from the group consisting of

[0071] (1) —CO(R¹⁹)— or —(R¹⁹)CO—, wherein R¹⁹ is a heterocycloalkyl, or a cycloalkyl group;

[0072] (2) —CONH— or —HNCO—; and

[0073] (3) —CO—;

[0074] (4) —SO₂—R¹⁹— or —R¹⁹—SO₂—;

[0075] (5) —SO₂—;

[0076] (6) —NH—SO₂— or —SO₂—NH—;

[0077] (7) —S—;

[0078] (8) —NH—CO—O— or —O—CO—NH—; or

[0079] (9) E is absent and R is bonded directly to Y; and

[0080] the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.

[0081] A particularly preferred compound for use in a contemplated process corresponds in structure to formula III, below, or a pharmaceutically acceptable salt thereof:

[0082] wherein

[0083] m, n, p, X, Z. Y and R¹⁴ are as defined above for formula II, and the R³ radical that is defined below is a sub-set of the previously discussed G-A-R-E-Y substituents.

[0084] Thus, R³ is a radical that is comprised of a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of a thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxy-phenoxy, 4-trifluoromethylphenoxy, 4-(trifluoromethylthio)-phenoxy, 4-(trifluoromethylthio)-thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy, 4-chloro-3-methylphenoxy, 3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy, 4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy, 3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, N-piperidyl, N-piperazinyl and a 4-benzyloxyphenoxy group.

[0085] A more particularly preferred compound for use in a contemplated process has a structure that corresponds to formula IV, below, or a pharmaceutically acceptable salt thereof:

[0086] wherein R³ is as defined above for formula I, more preferably as defined for formula II (wherein this R³ group is the G-A-R-E-Y substituent), and more preferably still as defined for formula III, and

[0087] Z is selected group the group consisting of O, S, NR⁶, SO, SO₂, and NSO₂R⁷,

[0088] wherein R⁶ is selected from the group consisting of hydrido, C₁-C₅-alkyl, C₁-C₅-alkanoyl, benzyl, benzoyl, C₃-C₅-alkynyl, C₃-C₅-alkenyl, C₁-C₃-alkoxy-C₁-C₄-alkyl, C₃-C₆-cycloalkyl, heteroaryl-C₁-C₆-alkyl, C₁-C₅-hydroxyalkyl, C₁-C₅-carboxyalkyl, C₁-C₅-alkoxy C₁-C₅-alkylcarbonyl, and NR⁸R⁹—C₁-C₅-alkylcarbonyl or NR⁸R⁹—C₁-C₅-alkyl wherein R⁸ and R⁹ are independently hydrido, C₁-C₅-alkyl, C₁-C₅-alkoxycarbonyl or aryl-C₁-C₅-alkoxycarbonyl, or NR⁸R⁹ together form a heterocyclic ring containing 5- to 8-atoms in the ring; and

[0089] R⁷ is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl and a C₁-C₆-hydroxyalkyl group.

[0090] A still more preferred group of compounds for use in a contemplated process correspond in structure to formula V, below, or a pharmaceutically acceptable salt thereof:

[0091] wherein

[0092] Z is as previously defined in formula IV;

[0093] W and Q are independently oxygen (O), NR⁶ or sulfur (S), and R⁶ is as defined in formula IV; and

[0094] q is zero or one such that when q is zero, the trifluoromethyl group is bonded directly to the depicted phenyl ring.

[0095] Further compounds of formula A are also particularly preferred. One group of these compounds corresponds in structure to formula B (including formulas B, B-A, B-1, B-1A, B-2, B-2A, B-3 and B-3A), formula VIC, and more still particularly to formula VIC-1 and formula VIC-2, and formula VIII, below. In those formulas, ring structure Q is a substituent of the depicted phenyl ring and can itself be substituted. Substituent Q including the depicted nitrogen atom is a heterocylic ring that contains 5- or 7-members, preferably 6-members, and can contain zero or one additional nitrogen atom. The substituents of Q such as A-R-E-Y, R-E-Y and E-Y are as defined before, and such a substituent is bonded at the 4-position relative to that depicted nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that depicted nitrogen when Q is a 5-membered ring. The remaining members of such a Q-beraing substituent (e.g., A-R-E-Y) are defined herein for the substituent G-A-R-E-Y. In addition, R²⁰, X, Y, Z, m, n, and p of the ring system and g are as before described, with Z preferably being O or NR⁶.

[0096] The compounds of formulas IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, below, are more particularly preferred among the compounds of formula VIC, formula VIC-1, formula VIC-2, and formula VIII. In those latter formulas, Z is as before described, with Z preferably being O or NR⁶, and substituent Q is a 6-membered ring, as is shown. The A moiety of the Q ring substituent -A-R-E-Y (e.g. of formula B or B-1) is preferably absent in some embodiments, as in the compounds of formulas XI through XII, whereas both moieties A and R of that substituent group are absent in compounds of formulas 1× through X. The moieties A, R, E and Y of the substituent group -A-R-E-Y are as defined for the substituent group -G-A-R-E-Y.

[0097] When used in a contemplated in a before-described process, a compound of formulas A, B, and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, a R²⁰ group is preferably —NH—O—R²² as defined above, and such a compound can also be present as a pharmaceutically acceptable salt. In addition, when so used, g is 2 in formulas B, VIC, VIC-1, VIC-2 and VII. The compounds of formulas A, B, and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII and their pharmaceutically acceptable salts are contemplated compounds of this invention.

[0098] The present invention also contemplates a precursor or intermediate compound that is useful in preparing a compound of formulas I-X. Such an intermediate compound corresponds in structure to formula VI, below:

[0099] wherein m, n, p, X, Z and Y are as defined above for formula II, g is zero, 1 or 2 and R²⁴ is R³ as defined in formulas I, III or IV, is the substituent G-A-R-E-Y of formula II (formula VIA) or is R³′, an aryl or heteroaryl group that is substituted with a coupling substituent reactive for coupling with another moiety (formula VIB), such as a nucleophilically displaceable leaving group, D.

[0100] Exemplary nucleophilically displaceable leaving groups, D, include a halo (fluoro, chloro, bromo, or iodo) nitro, azido, phenylsulfoxido, aryloxy, C₁-C₆-alkoxy, a C₁-C₆-alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C₁-C₆-alkyl or C₁-C₆-alkyl.

[0101] R²⁰ is (a)—O—R²¹, where R²¹ is selected from the group consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R²² wherein R²² is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C₁-C₆-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C₁-C₆-alkyl, aryl, or ar-C₁-C₆-alkyl or a mixture thereof, (c)—NH—O—R¹⁴, where R¹⁴ is hydrido, a pharmaceutically acceptable cation or C(W)R²⁵ where W is O (oxo) or S (thioxo) and R²⁵ is selected from the group consisting of an C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, ar-C₁-C₆-alkoxy, ar-C₁-C₆-alkyl, heteroaryl and amino C₁-C₆-alkyl group wherein the amino C₁-C₆-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ar-C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxycarbonyl, and C₁-C₆-alkanoyl radical, or (iii) wherein the amino C₁-C₆-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR²⁶R²⁷, where R²⁶ and R²⁷ are independently selected from the group consisting of a hydrido, C₁-C₆-alkyl, amino C₁-C₆-alkyl, hydroxy C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group, or R²⁶ and R²⁷ together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur.

[0102] A particularly preferred precursor intermediate to an intermediate compound of formula VI is an intermediate compound of formula VII

[0103] wherein m, n, p, g, X, Z, Y, D and R²⁰ are as defined above for formula VI.

[0104] Among the several benefits and advantages of the present invention are the provision of compounds and compositions effective as inhibitors of matrix metalloproteinase activity, the provision of such compounds and compositions that are effective for the inhibition of metalloproteinases implicated in diseases and disorders involving uncontrolled breakdown of connective tissue.

[0105] More particularly, a benefit of this invention is the provision of a compound and composition effective for selectively inhibiting certain metalloproteinases, such as one or more of MMP-2, MMP-9 and MMP-13, associated with pathological conditions such as, for example, rheumatoid arthritis osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's Disease, coronary thrombosis and bone disease.

[0106] An advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-2, MMP-9 or MMP-13 associated with such conditions with minimal side effects resulting from inhibition of other metalloproteinases, such as MMP-1, whose activity is necessary or desirable for normal body function.

[0107] Yet another advantage of the invention is the provision of a process for preparing such compounds.

[0108] Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.

[0109] A further advantage of the invention is the provision of a process for preparing such compositions.

[0110] Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.

DETAILED DESCRIPTION OF THE INVENTION

[0111] In accordance with the present invention, it has been discovered that certain aromatic sulfone hydroxamic acids (hydroxamates) are effective for inhibition of matrix metalloproteinases (“MMPs”) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that these certain aromatic sulfone hydroxamates are effective for inhibition of one or more enzymes such as MMP-2, MMP-9 and MMP-13, which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity. Included in that pathological activity is the assistance of tumors and tumor cells in the process of penetrating basement membrane, and developing a new or improved blood supply; i.e., angiogenesis.

[0112] Moreover, it has been discovered that these aromatic sulfone hydroxamates are selective in the inhibition of one or more of MMP-2, MMP-9 and MMP-13 without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that a contemplated aromatic sulfone hydroxamate of the invention, or a pharmaceutically acceptable salt thereof, is particularly active in inhibiting of one or more of MMP-2, MMP-9 and MMP-13 in an in vitro assay that is predictive of in vivo activity. In addition, while being selective for one or more of MMP-2, MMP-9 and MMP-13, a contemplated aromatic sulfone hydroxamate, or its salt, has a limited or minimal in vitro inhibitory effect on MMP-1.

[0113] There is thus a substantial difference in the activity of a compound used in a contemplated process toward one or more of MMP-2, MMP-9 and MMP-13 and MMP-1. This substantial difference is assayed using the in vitro inhibition assay discussed in the examples. A substantial difference in activity corresponds to a compound exhibiting an IC₅₀ value against one or more of MMP-2, MMP-9 and MMP-13 that is about 0.1 times that of the compound against MMP-1, and more preferably 0.01 times that against MMP-1 and most preferably 0.001 times that against MMP-1, or more. Indeed, some compounds exhibit selectivity differences measured by IC₅₀ values that exceed the bounds of the assay at the number 100,000-fold. These selectivities are illustrated in the Inhibition Tables hereinafter.

[0114] Put differently, a contemplated compound can inhibit the activity of MMP-2 compared to MMP-9 or MMP-13 and MMP-1. Similarly, a contemplated compound can inhibit the activity of MMP-13 and MMP-2, while exhibiting less inhibition against MMP-1 and MMP-9. In addition, a contemplated compound can inhibit the activity of a MMP enzyme, while having less of an effect on tumor necrosis factor release.

[0115] The advantages of the selectivity of a contemplated compound can be appreciated, without wishing to be bound by theory, by considering the therapeutic uses the compounds. For example, inhibition of MMP-1 is suggested to be undesirable due to its role as a housekeeping enzyme, helping to maintain normal connective tissue turnover and repair. Inhibition of MMP-1 can lead to toxicities or side effects such as such as joint or connective tissue deterioration and pain. On the other hand, MMP-13 has been suggested to be intimately involved in the destruction of joint components in diseases such as osteoarthritis. Thus, potent and selective inhibition of MMP-13 compared with inhibition MMP-1 is highly desirable because a MMP-13 inhibitor can have a positive effect on disease progression in a patient in addition to having an anti-inflammatory effect.

[0116] Inhibition of MMP-2 and MMP-9 can be desirable for inhibition of tumor growth, metastasis, invasion and/or angiogenesis. A profile of selective inhibition of MMP-2 and MMP-9 relative to MMP-1 can provide a therapeutic advantage.

[0117] Yet another advantage of a contemplated compound is the selectivity with respect to tumor necrosis factor release and/or tumor necrosis factor receptor release that provides the physician with another factor to help select the best drug for a particular patient. While not wishing to be bound by theory, it is believed that there are several factors to this type of selectivity to be considered.

[0118] The first is that presence of tumor necrosis factor can be desirable for the control of cancer in the organism, so long as TNF is not present in a toxic excess. Thus, uncontrolled inhibition of release of TNF cad be counterproductive and actually can be considered an adverse side effect even in cancer patients. In addition, selectivity with respect to inhibition of the release of the tumor necrosis factor receptor can also be desirable. The presence of that receptor can be desirable for maintaining a controlled tumor necrosis level in the mammal by binding excess TNF.

[0119] A contemplated selective MMP inhibitor compound useful in a contemplated process can be administered to by various routes and provide adequate therapeutic blood levels of enzymatically active inhibitor. A compound can be administered, for example, by the oral (IG, PO) or intravenous (IV) routes. Oral administration is advantageous if the patient is ambulatory, not hospitalized, physically able and sufficiently-responsible to take drug at the required intervals. This is true even if the person is being treated with more than one drug for one or more diseases. On the other hand, IV drug administration is an advantage in a hospital setting wherein the dose and thus the blood levels can well controlled. A contemplated inhibitor can also be formulated for IM administration if desired. This route of administration can be desirable for the administration of prodrugs or regular drug delivery to patients that are either physically weak or have a poor compliance record or require constant drug blood levels.

[0120] Thus, in one embodiment, the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor, or a pharmaceutically acceptable salt thereof, in an effective amount to a host mammal having a condition associated with pathological matrix metalloprotease activity. A contemplated aromatic sulfone hydroxamate inhibitor compound useful in such a process inhibits the activity of one or more of MMP-2, MMP-9 and MMP-13, and exhibits substantially less inhibitory activity against at least MMP-1 in the in vitro assay noted above and discussed in detail hereinbelow. An aromatic sulfone hydroxamate inhibitor compound for use in a contemplated process corresponds in structure to formula I, below:

[0121] wherein

[0122] In one embodiment, R¹ and R² are both hydrido. In another embodiment, R¹ and R² together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring that are oxygen, sulfur or nitrogen.

[0123] It is preferred that R¹ and R² together with the atoms to which they are bonded form a five-to eight-membered ring that contains one or two heteroatoms in the ring, although R¹ and R² together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms. The heterocyclic ring can itself also be substituted with up to six C₁-C₆-alkyl groups or groups that comprise a another 5- to 8-membered carbocyclic or heterocyclic ring, an amino group, or contain one or two oxo (carbonyl) groups.

[0124] R³ in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical. That R³ radical is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic.

[0125] The substituent of which R³ is comprised itself is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,

[0126] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino

[0127] wherein the carboxamido nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group,

[0128] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl-group

[0129] wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring. A compound of formula I can also be used in the form of a pharmaceutically acceptable salt.

[0130] The R³ radical has a length that is greater than that of a pentyl group [a —(CH₂)₄CH₃ chain], is more preferably greater than about the length of a hexyl group [a —(CH₂)₅CH₃ chain), and most preferably is greater than about the length of an octyl group [a —(CH₂)₇CH₃ chain]. A R³ group has a length that is less than that of an icosyl group [eicosyl; a —(CH₂)₁₉CH₃ chain), and more preferably, a length that is less than that of a stearyl group [a —(CH₂)₁₇CH₃ chain). When rotated about an axis drawn through the SO₂-bonded 1-position and the substituent-bonded 4-position of a 6-membered ring or the SO₂-bonded 1-position and substituent-bonded 3- or 4-position of a 5-membered ring, a contemplated R³ radical defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about two phenyl rings in a direction transverse to that axis to rotation.

[0131] A compound of formula I is a compound of more general formula A, wherein R³, R¹ and R² are as defined before and R²⁰ is defined below.

[0132] The substituent R²⁰ is (a)—O—R²¹, where R²¹ is selected from the group consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R²² wherein R²² is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C₁-C₆-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C₁-C₆-alkyl, aryl, or ar-C₁-C₆-alkyl or a mixture thereof, (c) —NH—O—R¹⁴, where R¹⁴ is hydrido, a pharmaceutically acceptable cation or C(W)R²⁵ where W is 0 (oxo) or S (thioxo) and R²⁵ is selected from the group consisting of an C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, ar-C₁-C₆-alkoxy, ar-C₁-C₆-alkyl, heteroaryl and amino C₁-C₆-alkyl group wherein the amino C₁-C₆-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ar-C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxycarbonyl, and C₁-C₆-alkanoyl radical, or (iii) wherein the amino C₁-C₆-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d)—NR²⁶R²⁷, where R²⁶ and R²⁷ are independently selected from the group consisting of a hydrido, C₁-C₆-alkyl, amino C₁-C₆-alkyl, hydroxy C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group, or R²⁶ and R²⁷ together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur.

[0133] Several exemplary R¹ and R² groups that together form a contemplated heterocyclic ring are shown in the Tables that follow hereinafter, as well as in the descriptions of those 5- to 8-membered rings and the specific Examples, as are several contemplated aromatic sulfone hydroxamic acid compounds.

[0134] In more preferred practice, R¹ and R² of formula I or formula A together with the atom to which they are bonded form a 5- to 8-membered ring that contains one, two or three heteroatoms. Most preferably, that ring is a 6-membered ring that contains one heteroatom located at the 4-position relative to the position at which the SO₂ group is bonded. Other preferred compounds for use in a contemplated process correspond in structure to one or more of formulas II, III, IV or V, which are discussed hereinafter.

[0135] In one embodiment, a preferred compound used in a contemplated process has a structure that corresponds to formula II, below:

[0136] wherein

[0137] R¹⁴ is hydrido, a pharmaceutically acceptable cation or C(W)R¹⁵ where W is O or S and R¹⁵ is selected from the group consisting of an C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, ar-C₁-C₆-alkoxy, ar-C₁-C₆-alkyl, heteroaryl and amino C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ar-C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxycarbonyl, and C₁-C₆-alkanoyl radical, or (iii) wherein the amino C₁-C₆-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;

[0138] m is zero, 1 or 2;

[0139] n is zero, 1 or 2;

[0140] p is zero, 1 or 2;

[0141] the sum of m+n+p=1, 2, 3 or 4;

[0142] (a) one of X, Y and Z is selected from the group consisting of C(O), NR⁶, O, S, S(O), S(O)₂ and NS(O)₂R⁷, and the remaining two of X, Y and Z are CR⁸R⁹, and CR¹⁰R¹¹, or

[0143] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR⁶C(O), NR⁶S(O), NR⁶S(O)₂, NR⁶S, NR⁶O, SS, NR⁶NR⁶ and OC(O), with the remaining one of X, Y and Z being CR⁸R⁹, or

[0144] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of

[0145] wherein wavy lines are bonds to the atoms of the depicted ring;

[0146] R⁶ and R⁶′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkylcarbonyl, hydroxycarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C₁-C₆-alkylcarbonylcarbonyl, R⁸R⁹-aminocarbonylcarbonyl, C₁-C₆-alkanoyl, aryl-C₁-C₆-alkyl, aroyl, bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)-C₁-C₆-alkyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-perfluoroalkyl, C₁-C₆-trifluoromethylalkyl, C₁-C₆-perfluoroalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C₃-C₈-heterocycloalkyl, C₃-C₈-heterocycloalkylcarbonyl, aryl, C₅-C₆-heterocyclo, C₅-C₆-heteroaryl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, arylsulfonyl, C₁-C₆-alkylsulfonyl, C₅-C₆-heteroarylsulfonyl, carboxy-C₁-C₆-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl, aminocarbonyl, C₁-C₆-alkyl(R⁸N)iminocarbonyl, aryl(R⁸N)iminocarbonyl, C₅-C₆-heterocyclo(R⁸N)iminocarbonyl, arylthio-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₃-C₆-alkenyl, C₁-C₄-alkylthio-C₃-C₆-alkenyl, C₅-C₆-heteroaryl-C₁-C₆-alkyl, halo-C₁-C₆-alkanoyl, hydroxy-C₁-C₆-alkanoyl, thio]-C₁-C₆-alkanoyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkoxycarbonyl, aryloxycarbonyl, NR⁸R⁹—(R⁸)iminomethyl; NR⁸R⁹—C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, R⁸R⁹-aminocarbonyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkylcarbonyl, hydroxyaminocarbonyl, R⁸R⁹-aminosulfonyl, R⁸R⁹-aminosulfon-C₁-C₆-alkyl, R⁸R⁹-amino-C₁-C₆-alkylsulfonyl and an R⁸R⁹-amino-C₁-C₆-alkyl group;

[0147] R⁷ is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl and a C₁-C₆-hydroxyalkyl group;

[0148] R⁸ and R⁹ and R¹⁰ and R¹¹ are independently selected from the group consisting of a hydrido, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, ar-C₁-C₆-alkyl, heteroaryl, heteroar-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, aralkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl and C₁-C₆-alkanoyl, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹ and the carbon to which they are bonded form a carbonyl group, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹, or R⁸ and R¹⁰ together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R⁸ and R⁹ or R¹⁰ and R¹¹ is hydroxy;

[0149] R¹² and R¹²′ are independently selected from the group consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, heteroaryl, heteroaralkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl and C₁-C₆-alkanoyl;

[0150] R¹³ is selected from the group consisting of a hydrido, benzyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl and a C₁-C₆-hydroxyalkyl group; and

[0151] G-A-R-E-Y is a substituent that preferably as a length greater than that of a pentyl group, and ore preferably has a length greater than that of a hexyl group. The substituent G-A-R-E-Y preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent:

[0152] G is an aryl or heteroaryl group;

[0153] A is selected from the group consisting of

[0154] (1) —O—;

[0155] (2) —S—;

[0156] (3) —NR¹⁷—;

[0157] (4) —CO—N(R¹⁷) or —N(R¹⁷)—CO—, wherein R¹⁷ is hydrogen, C₁-C₄-alkyl, or phenyl;

[0158] (5) —CO—O— or —O—CO—;

[0159] (6) —O—CO—O—;

[0160] (7) —HC═CH—;

[0161] (8) —NH—CO—NH—;

[0162] (9) —C≡C—;

[0163] (10) —NH—CO—O— or —O—CO—NH—;

[0164] (11) —N═N—;

[0165] (12) —NH—NH—; and

[0166] (13) —CS—N(R¹⁸)— or —N(R¹⁸)—CS—, wherein

[0167] R¹⁸ is hydrogen C₁-C₄-alkyl, or phenyl; or

[0168] (14) A is absent and G is bonded directly to R;

[0169] R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C₁-C₂-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group, and R is other than alkyl or alkoxyalkyl when A is —O— or —S—;

[0170] E is selected from the group consisting of

[0171] (1) —CO(R¹⁹)— or —(R¹⁹)CO—, wherein R¹⁹ is a heterocycloalkyl, or a cycloalkyl group;

[0172] (2) —CONH— or —HNCO—; and

[0173] (3) —CO—;

[0174] (4) —SO₂—R¹⁹— or —R¹⁹—SO₂—;

[0175] (5) —SO₂—;

[0176] (6) —NH—SO₂— or —SO₂—NH—;

[0177] (7) —S—;

[0178] (8) —NH—CO—O— or —O—CO—NH—; or

[0179] (9) E is absent and R is bonded directly to Y; and

[0180] the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group.

[0181] The substituent -G-A-R-E-Y preferably contains two to four carbocyclic or heterocyclic rings, including the aryl or heteroaryl group, G. More preferably, each of those rings is 6-membered. Additional separate preferences for a compound of formula II include: (a) that A is —O— or —S—, (b) R is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, (c) E is absent, and (d) Y is selected from the group consisting of hydrido, an alkyl, alkoxy, perfluoroalkoxy and a perfluoroalkylthio group.

[0182] A more preferred compound for use in a contemplated process has a structure that corresponds to formula III, below:

[0183] wherein R³ is a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of a thiophenoxy, 4-chloro-phenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluoro-phenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoro-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-(trifluoromethylthio)phenoxy, 4-(trifluoromethyl-thio)thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy, 4-chloro-3-methylphenoxy, 3-methyl-phenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy, 4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy, 3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, and a 4-benzyloxyphenoxy group;

[0184] R¹⁴ is hydrido, a pharmaceutically acceptable cation or C(W)R¹⁵ where W is O or S and R¹⁵ is selected from the group consisting of an C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, ar-C₁-C₆-alkoxy, ar-C₁-C₆-alkyl, heteroaryl and amino C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ar-C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxycarbonyl, and a C₁-C₆-alkanoyl radical, or (iii) wherein the amino C₁-C₆-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;

[0185] m is zero, 1 or 2;

[0186] n is zero, 1 or 2;

[0187] p is zero, 1 or 2;

[0188] the sum of m+n+p 1, 2, 3 or 4;

[0189] (a) one of X, Y and Z is selected from the group consisting of C(O), NR⁶, O, S, S(O), S(O)₂ and NS(O)₂R⁷, and the remaining two of X, Y and Z are CR⁸R⁹, and CR¹⁰R¹¹, or

[0190] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR⁶C(O), NR⁶S(O), NR⁶S(O)₂, NR⁶S, NR⁶O, SS, NR⁶NR⁶ and OC(O), with the remaining one of X, Y and Z being CR⁸R⁹, or

[0191] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of

[0192] wherein wavy lines are bonds to the atoms of the depicted ring;

[0193] R⁶ and R⁶′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkylcarbonyl, hydroxycarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C₁-C₆-alkylcarbonylcarbonyl, R⁸R⁹-aminocarbonylcarbonyl, C₁-C₆-alkanoyl, aryl-C₁-C₆-alkyl, aroyl, bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)-C₁-C₆-alkyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-perfluoroalkyl, C₁-C₆-trifluoromethylalkyl, C₁-C₆-perfluoroalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆ alkyl, C₃-C₆-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C₃-C₈-heterocycloalkyl, C₃-C₈-heterocycloalkylcarbonyl, aryl, C₅-C₆-heterocyclo, C₅-C₆-heteroaryl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, arylsulfonyl, C₁-C₆-alkylsulfonyl, C₅-C₆-heteroarylsulfonyl, carboxy-C₁-C₆-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl, aminocarbonyl, C₁-C₆-alkyl(R⁸N)iminocarbonyl, aryl(R⁸N)iminocarbonyl, C₅-C₆-heterocyclo(R⁸N)iminocarbonyl, arylthio-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₃-C₆-alkenyl, C₁-C₄-alkylthio-C₃-C₆-alkenyl, C₅-C₆-heteroaryl-C₁-C₆-alkyl, halo-C₁-C₆-alkanoyl, hydroxy-C₁-C₆-alkanoyl, thiol-C₁-C₆-alkanoyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkoxycarbonyl, aryloxycarbonyl, NR⁸R⁹—(R⁸)iminomethyl, NR⁸R⁹—C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, R⁸R⁹-aminocarbonyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkylcarbonyl, hydroxyaminocarbonyl, R⁸R⁹-aminosulfonyl, R⁸R⁹-aminosulfon-C₁-C₆-alkyl, R⁸R⁹-amino-C₁-C₆-alkylsulfonyl and an R⁸R⁹-amino-C₁-C₆-alkyl group;

[0194] R⁷ is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl and a C₁-C₆-hydroxyalkyl group;

[0195] R⁸ and R⁹ and R¹⁰ and R¹¹ are independently selected from the group consisting of a hydrido, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, ar-C₁-C₆-alkyl, heteroaryl, heteroar-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, aralkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl and C₁-C₆-alkanoyl, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹ and the carbon to which they are bonded form a carbonyl group, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹, or R⁸ and R¹⁰ together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R⁸ and R⁹ or R¹⁰ and R¹¹ is hydroxy;

[0196] R¹² and R¹²′ are independently selected from the group consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, heteroaryl, heteroaralkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thio]-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl and C₁-C₆-alkanoyl; and

[0197] R¹³ is selected from the group consisting of a hydrido, benzyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl and a C₁-C₆-hydroxyalkyl group. Again, the use of a compound of formula III as a pharmaceutically acceptable salt is also contemplated.

[0198] Preferences related to a compound of formula III that also apply to a compound of formula II include the following, which are independently preferred: (a) the sum of m+n+p=1 or 2, and more preferably 2; (b) Z is O, S or NR⁶; (c) R⁶ is selected from the group consisting of C₃-C₆-cycloalkyl, C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, aminosulfonyl, heteroaryl-C₁-C₆-alkyl, aryloxycarbonyl, and C₁-C₆-alkoxycarbonyl; and (d) m=n=zero, p=1, and Y is NR⁶. Another preference for a compound of both of formulas II and III is that R¹⁴ be hydrido, or that W of the C(W)R¹⁵ pro-drug form be 0 and R¹⁵ be a C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, or aryloxy group.

[0199] A still more preferred compound for use in a contemplated process corresponds in structure to formula IV, below:

[0200] Here, R³ is as defined above as to formulas I, III and more preferably as defined as to formula II (wherein the R³ radical is the substituent G-A-R-E-Y). Most preferably, R³ is as defined in formula III.

[0201] Z is selected group the group consisting of O, S, NR⁶, SO, SO₂, and NSO₂R⁷,

[0202] wherein R⁶ is selected from the group consisting of hydrido, C₁-C₅-alkyl, C₁-C₅-alkanoyl, benzyl, benzoyl, C₃-C₅-alkynyl, C₃-C₅-alkenyl, C₁-C₃-alkoxy-C₁-C₄-alkyl, C₃-C₆-cycloalkyl, heteroaryl-C₁-C₆-alkyl, C₁-C₅-hydroxyalkyl, C₁-C₅-carboxyalkyl, C₁-C₅-alkoxy C₁-C₅-alkylcarbonyl, and NR⁸R⁹—C₁-C₅-alkylcarbonyl or NR⁸R⁹—C₁-C₅-alkyl wherein R⁸ and R⁹ are independently hydrido, C₁-C₅-alkyl, C₁-C₅-alkoxycarbonyl or aryl-C₁-C₅-alkoxycarbonyl, or NR⁸R⁹ together form a heterocyclic ring containing 5- to 8-atoms in the ring; and

[0203] R⁷ is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl and a C₁-C₆-hydroxyalkyl group. Most preferably, Z is O or NR⁶. Here too, the use of a compound of formula IV as a pharmaceutically acceptable salt is contemplated.

[0204] A still more preferred group of contemplated compounds for use in a contemplated process correspond in structure to formula V, below;

[0205] wherein

[0206] Z is as previously defined for formula IV;

[0207] W and Q are independently oxygen (O), NR⁶ or sulfur (S), and R⁶ is as defined in formula IV; and

[0208] q is zero or one such that when q is zero, Q is absent and the trifluoromethyl group is bonded directly to the depicted phenyl ring. Here again, the use of a compound of formula IV as a pharmaceutically acceptable salt is contemplated.

[0209] Further compounds of formula A are also particularly preferred. One group of these compounds corresponds in structure to formula B, formula VIC, and more still particularly to formula VIC-1 and formula VIC-2, and formula VIII, below. In those formulas, ring structure Q including the depicted nitrogen atom is a heterocylic ring that contains 5- or 7-members, preferably 6-members, and can contain zero or one nitrogen atom in addition to that depicted. The members of substituent -A-R-E-Y (or —R-E-Y or -E-Y) are as defined elsewhere in the definition of the members of the substituent -G-A-R-E-Y. Furthermore, substituent -A-R-E-Y (or substituent —R-E-Y or -E-Y) is bonded at the 4-position relative to that depicted nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that depicted nitrogen when Q is a 5-membered ring. Still fruther, R²⁰, X, Y, Z, m, n, and p of the ring system and g are as before described.

[0210] More particularly preferred among the compounds of formula VIC, formula VIC-1, formula VIC-2, and formula VIII, are the compounds of formulas IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, below, wherein Z is as before described and the members of substituent group -E-Y and —R-E-Y are as defined for the substituent group -G-A-R-E-Y.

[0211] The use of a compound of formulas A and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2 and X, or a pharmaceutically acceptable salt of one of those compounds is contemplated in a before-described process. In addition, the compounds of those formulas and their pharmaceutically acceptable salts are contemplated compounds of this invention.

[0212] Particularly preferred compounds within the group defined by formula B have the structural formulas shown below:

[0213] Several particularly preferred compounds whose structures correspond to formulas I through XII are illustrated in the Tables and examples provided hereinafter.

[0214] As was noted before, the compounds of formulas I-XII, and their pharmaceutically acceptable salts are themselves contemplated compounds of the invention.

[0215] In preferred practice, an SO₂-linked R³ radical is an aryl or heteroaryl group that is a 5- or 6-membered single-ring that is itself substituted with one other single-ringed aryl or heteroaryl group or, with an alkyl or alkoxy group having a chain length of 3 to about 16 carbon atoms (and more preferably a length of up to about 14 carbon atoms), a phenoxy group, a thiophenoxy (C₆H₅—S—] group, a phenylazo [C₆H₅—N₂—] group, a N-piperidyl [C₅H₁₀N—] group, a N-piperazyl [NC₄H₉N—] group or a benzamido [—NHC(O)C₆H₅] group. The SO₂-linked single-ringed aryl or heteroaryl R³ group here is substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring.

[0216] The SO₂-linked aryl or heteroaryl group of a R³ radical is preferably itself substituted at the 4-position when a 6-membered ring or the 3- or 4-position when a 5-membered ring. A particularly preferred substituent is a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, N-piperidyl, N-piperazyl or benzamido group that is unsubstituted or can itself be substituted.

[0217] The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding as compared to formalized ring numbering positions used in heteroaryl nomenclature, as is discussed further hereinbelow. Here, single atoms such as halogen moieties (fluoro, chloro, bromo, or iodo) or substituents that contain one to a chain length of about five atoms other than hydrogen such as phenyl, C₁-C₄ alkyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethyl or carboxyethyl groups are preferred, although longer substituents can be accommodated up to a total length of an icosyl group.

[0218] Exemplary particularly preferred substituted SO₂-linked R³ radicals include 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl, 4-[(4′-trifluoromethylthio)thiophenyl]phenyl, 4-[(4′-trifluoromethyl)phenoxy]phenyl, 4-[(4′-trifluoromethyl)thiophenyl]phenyl, 4-[(4′-trifluoromethoxy)phenoxy]phenyl, 4-[(4′-trifluoromethoxy)thiophenyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-acetyl)N-piperazyl]phenyl and 4-(benzamido)phenyl.

[0219] Inasmuch as a contemplated SO₂-linked aryl or heteroaryl radical of an R³ group is itself preferably substituted with a 6-membered ring, two nomenclature systems are used together herein for ease in understanding substituent positions. The first system uses position numbers for the ring directly bonded to the SO₂-group, whereas the second system uses ortho, meta or para for the position of one or more substituents of a 6-membered ring bonded to a SO₂-linked aryl or heteroaryl radical. Although ortho, meta and para positional nomenclature is normally not used with aliphatic ring systems, it is believed more readily understood for describing the present compounds when used in conjunction with the numerical system for the first ring bonded to the SO₂-group. When a R³ radical is other than a 6-membered ring, substituent positions are numbered from the position of linkage to the aromatic or heteroaromatic ring. Formal chemical nomenclature is used in naming particular compounds.

[0220] Thus, the 1-position of an above-discussed SO₂-linked aryl or heteroaryl group is the position at which the SO₂-group is bonded to the ring. The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding from the SO₂-linkage as compared to formalized ring numbering positions used in heteroaryl nomenclature.

[0221] When examined along its longest chain of atoms, an R³ radical including its own substituent has a total length that is greater than a saturated chain of five carbon atoms (a pentyl group), and preferably has a length greater than that of a saturated chain of six carbon atoms (a hexyl group); i.e., a length of about a heptyl chain or longer. An R³ radical also has a length that is less than that of a saturated chain of about 20 carbon atoms [an icosyl group (icosyl was formerly spelled eicosyl)] and more preferably about 18 carbon atoms (a stearyl group). Most preferably, the length of R³ is about that of an 8 to about 12 carbon atom chain, even though many more atoms may be present in ring structures or substituents. This length requirement is discussed further below.

[0222] Looked at more generally, and aside from specific moieties from which it is constructed, an R³ radical (group or moiety) has a length that is greater than that of a pentyl group. Such an R³ radical also has a length that is less than that of an icosyl (didecyl) group. That is to say that R³ is a radical having a minimal length longer that a saturated five carbon chain, and preferably greater than a hexyl group, but is shorter than the length of a saturated twenty carbon atom chain, and preferably shorter than an eighteen carbon chain. Most preferably, R³ has a length greater than that of an octyl group and less than that of a lauryl group.

[0223] More specifically, an R³ group has a minimal length of a hexyl group only when that substituent is comprised of two rings that can be fused or simply covalently linked together by exocyclic bonding. When R³ does not contain two linked or fused rings, e.g., where a R³ radical includes an alkyl or second, third or fourth ring substituent, R³ has a length that is greater than that of a hexyl group. Exemplary of such two ring R³ groups are a 2-naphthyl group or a 2-quinolinyl group (each with a six carbon chain length) and 8-purinyl (with a five carbon atom chain length). Without wishing to be bound by theory, it is believed that the presence of multiple rings in R³ enhances selectivity of the enzyme activity inhibitor profile.

[0224] The radical chain lengths are measured along the longest linear atom chain in the radical, following the skeletal atoms around a ring where necessary. Each atom in the chain, e.g. carbon, oxygen, sulfur or nitrogen, is presumed to be carbon for ease in calculation.

[0225] Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a desired, usually staggered, chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values. Radical (substituent) lengths can also be determined somewhat less exactly by assuming that all atoms have bond lengths saturated carbon, that unsaturated bonds have the same lengths as saturated bonds and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred. For example, a phenyl or pyridyl group has a length of a four carbon chain, as does a propoxy group, whereas a biphenyl group has a length of about an eight carbon chain using such a measurement mode.

[0226] In addition, a R³ group when rotated about an axis drawn through the SO₂-bonded 1-position and the 4-position of a 6-membered ring or the SO₂-bonded position and substituent-bonded 3- or 4-position of a 5-membered ring defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about two phenyl rings in a direction transverse to that axis to rotation.

[0227] Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized R³ group when examined using the above rotational width criterion as well as the before-discussed criterion. On the other hand, a 1-naphthyl group or a 7- or 9-purinyl group is too wide upon rotation and is excluded from being an R³ group.

[0228] As a consequence of these length and width requirements, R³ radicals such as 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl, 4-[(4′-trifluoromethylthio)thiophenyl]phenyl, 4-[(4′-trifluoromethyl)phenoxy]phenyl, 4-[(4′-trifluoromethyl)thiophenyl]phenyl, 4-[(4′-trifluoromethoxy)phenoxy]phenyl, 4-[(4′-trifluoromethoxy)thiophenyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-acetyl)N-piperazyl]phenyl and 4-(benzamido)phenyl are particularly preferred R³ radicals. Those substituents can themselves also be substituted in the second ring from the SO₂ group at the meta- or para-position or both with a single atom or a substituent containing a longest chain length that is preferably of up to five atoms, excluding hydrogen.

[0229] Without wishing to be bound by theory, the length of a R³ radical substituent bonded to the SO₂ group is believed to play a role in the overall activity of a contemplated inhibitor compound against MMP enzymes generally. The length of the R³ radical group also appears to play a role in the selective activity of an inhibitor compound against particular MMP enzymes.

[0230] In particularly preferred practice, R³ is a PhR²³ group, wherein Ph is phenyl. The phenyl ring (Ph) of a PhR²³ group is substituted at its para-position (4-position) by an R²³ group that can be another single-ringed aryl or heteroaryl group, a piperidyl group, a piperazinyl group, a phenoxy group, a thiophenoxy [C₆H₅—S—) group, a phenylazo [C₆H₅—N₂—] group or a benzamido [—NHC(O)C₆H₅] group.

[0231] In one embodiment of a particularly preferred aromatic sulfone hydroxamate inhibitor compound, an R²³ substituent is phenoxy and is itself substituted at its own para-position with a moiety that is selected from the group consisting of a halogen, a C₁-C₄ alkoxy group, a C₁-C₄ alkyl group, a dimethylamino group, a carboxyl C₁-C₃ alkylene group, a C₁-C₄ alkoxy carbonyl C₁-C₃ alkylene group, a trifluoromethylthio group, a trifluoromethoxy group, a trifluoromethyl group and a carboxamido C₁-C₃ alkylene group, or is substituted at the meta- and para-positions by a methylenedioxy group. It is to be understood that any R²³ substituent can be substituted with a moiety from the above list. Such substitution at the para-position is preferred.

[0232] The present invention also contemplates a compound that corresponds in structure to formula VI, below, that is useful in preparing a compound of formulas I-V, as well as as an active MMP-inhibiting compound and as a pro-drug form of an inhibitor.

[0233] wherein g is zero, 1 or 2;

[0234] R²⁰ is (a)—O—R²¹, where R²¹ is selected from the group consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R²² wherein R²² is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C₁-C₆-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C₁-C₆-alkyl, aryl, or ar-C₁-C₆-alkyl or a mixture thereof, (c)—NH—O—R¹⁴, where R¹⁴ is hydrido, a pharmaceutically acceptable cation or C(W)R²⁵ where W is O (oxo) or S (thioxo) and R²⁵ is selected from the group consisting of an C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, ar-C₁-C₆-alkoxy, ar-C₁-C₆-alkyl, heteroaryl and amino C₁-C₆-alkyl group wherein the amino C₁-C₆-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, ar-C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxycarbonyl, and C₁-C₆-alkanoyl radical, or (iii) wherein the amino C₁-C₆-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR²⁶R²⁷, where R²⁶ and R²⁷ are independently selected from the group consisting of a hydrido, C₁-C₆-alkyl, amino C₁-C₆-alkyl, hydroxy C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group, or R²⁶ and R²⁷ together with the depicted nitrogen atom form a 5- to 7-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur;

[0235] m is zero, 1 or 2;

[0236] n is zero, 1 or 2;

[0237] p is zero, 1 or 2;

[0238] the sum of m+n+p=1, 2, 3 or 4;

[0239] (a) one of X, Y and Z is selected from the group consisting of C(O), NR⁶, O, S, S(O), S(O)₂ and NS(O)₂R⁷, and the remaining two of X, Y and Z are CR⁸R⁹, and CR¹⁰R¹¹, or

[0240] (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR⁶C(O), NR⁶S(O), NR⁶S(O)₂, NR⁶S, NR⁶O, SS, NR⁶NR⁶ and OC(O), with the remaining one of X, Y and Z being CR⁸R⁹, or

[0241] (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of

[0242] wherein wavy lines are bonds to the atoms of the depicted ring;

[0243] R⁶ and R⁶ are independently selected from the group consisting of hydrido, formyl, sulfonic-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkylcarbonyl, hydroxycarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C₁-C₆-alkylcarbonylcarbonyl, R⁸R⁹-aminocarbonylcarbonyl, C₁-C₆-alkanoyl, aryl-C₁-C₆-alkyl, aroyl, bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)-C₁-C₆-alkyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-perfluoroalkyl, C₁-C₆-trifluoromethylalkyl, C₁-C₆-perfluoroalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C₃-C₈-heterocycloalkyl, C₃-C₈-heterocycloalkylcarbonyl, aryl, C₅-C₆-heterocyclo, C₅-C₆-heteroaryl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, arylsulfonyl, C₁-C₆-alkylsulfonyl, C₅-C₆-heteroarylsulfonyl, carboxy-C₁-C₆-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl, aminocarbonyl, C₁-C₆-alkyl(R⁸N)iminocarbonyl, aryl(R⁸N)iminocarbonyl, C₅-C₆-heterocyclo(R⁸N)iminocarbonyl, arylthio-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₃-C₆-alkenyl, C₁-C₄-alkylthio-C₃-C₆-alkenyl, C₅-C₆-heteroaryl-C₁-C₆-alkyl, halo-C₁-C₆-alkanoyl, hydroxy-C₁-C₆-alkanoyl, thio]-C₁-C₆-alkanoyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkoxycarbonyl, aryloxycarbonyl, NR⁸R⁹—(R⁸)iminomethyl, NR⁸R⁹—C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, R⁸R⁹-aminocarbonyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkylcarbonyl, hydroxyaminocarbonyl, R⁸R⁹-aminosulfonyl, R⁸R⁹-aminosulfon-C₁-C₆-alkyl, R⁸R⁹-amino-C₁-C₆-alkylsulfonyl and an R⁸R⁹-amino-C₁-C₆-alkyl group;

[0244] R⁷ is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl and a C₁-C₆-hydroxyalkyl group;

[0245] R⁸ and R⁹ and R¹⁰ and R¹¹ are independently selected from the group consisting of a hydrido, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, ar-C₁-C₆-alkyl, heteroaryl, heteroar-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, aralkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl and C₁-C₆-alkanoyl, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹ and the carbon to which they are bonded form a carbonyl group, or wherein R⁸ and R⁹ or R¹⁰ and R¹¹, or R⁸ and R¹⁰ together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R⁸ and R⁹ or R¹⁰ and R¹¹ is hydroxy;

[0246] R¹² and R¹²′ are independently selected from the group consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl, heteroaryl, heteroaralkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylar-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl and an amino-C₁-C₆-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C₁-C₆-alkyl, ar-C₁-C₆-alkyl, cycloalkyl and C₁-C₆-alkanoyl;

[0247] R¹³ is selected from the group consisting of a hydrido, benzyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl and a C₁-C₆-hydroxyalkyl group; and

[0248] R²⁴ is R³ as defined in formulas I, III, IV or is the substituent G-A-R-E-Y of formula II (formula VIA). Alternatively, R²⁴ is R³′, an aryl or heteroaryl group that is substituted with a coupling substituent reactive for coupling with another moiety (formula VIB), such as a nucleophilically displaceable leaving group, D.

[0249] Exemplary nucleophilically displaceable leaving groups, D, include a halo (fluoro, chloro, bromo, or iodo) nitro, azido, phenylsulfoxido, aryloxy, C₁-C₆-alkoxy, a C₁-C₆-alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C₁-C₆-alkyl or C₁-C₆-alkyl. Additional coupling substituents include, without limitation, a hydroxyl group and an amino group that can be coupled with carbonyl-containing moieties to form esters, urethanes, carbonates, amides and ureas. Similarly, a carboxyl coupling substituent can be used to form an ester, thioester or amide. Thus, a coupling substituent is useful in converting a coupling substituent-containing aryl or heteroaryl group into a substituent such as a G-A-R-E-Y substituent discussed hereinabove by the formation of a covalent bond.

[0250] A compound of formula VI can be coupled with another moiety at the R³′ coupling substituent to form a compound whose newly formed R³ group is that of formulas I, III, IV or -G-A-R-E-Y. Exemplary of such couplings are the nucleophilic displacement to form ethers and thioethers, as well as the formation of ester, amide, urea, carbonate, urethane and the like linkages.

[0251] More particularly, where a R²⁰ group is —O—R²¹, with R²¹ being selected from the group consisting of a hydrido, C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl group and a pharmaceutically acceptable cation, a precursor carboxylic acid or ester compound is defined that can be readily transformed into a hydroxamic acid, as is illustrated in several examples hereinafter.

[0252] Where a R²⁰ group is —NH—O—R²², wherein R²² is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C₁-C₆-alkoxy, trisubstituted silyl group, an o-nitrophenyl group, or a peptide synthesis resin and the like, a synthetic intermediate is typically defined. In these compounds, a trisubstituted silyl group is substituted with C₁-C₆-alkyl, aryl, ar-C₁-C₆-alkyl or a mixture thereof, such as a trimethylsilyl, dimethylisopropylsilyl, triethylsilyl, triphenylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl, a tribenzylsilyl group, and the like. Exemplary trisubstituted silyl protecting groups and their uses are discussed at several places in Greene et al., Protective Groups In Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York (1991).

[0253] A contemplated peptide synthesis resin is solid phase support also known as a so-called Merrifield's Peptide Resin that is adapted for synthesis and selective release of hydroxamic acid derivatives as is commercially available from Sigma Chemical Co., St. Louis, MO. An exemplary peptide synthesis resin so adapted and its use in the synthesis of hydroxamic acid derivatives is discussed in Floyd et al., Tetrahedron Let., 37(44):8048-8048(1996).

[0254] A 2-tetrahydropyranyl (THP) protecting group is a particularly preferred selectively removable protecting group. A contemplated THP-protected hydroxamate compound of formula VII can be prepared by reacting the carboxylic acid precursor compound of formula VII [where R²⁰ is —O—R²¹ and R²¹ is a hydrido group] in water with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine in the presence of N-methylmorpholine, N-hydroxybenzotriazole hydrate and a water-soluble carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The THP protecting group is readily removable in an aqueous acid solution such as an aqueous mixture of p-toluenesulfonic acid or HCl and acetonitrile or methanol. An illustrative THP-protected compound corresponds in structure to formula VIIB, below, wherein m, n, p, g, X, Z. Y, and D are as defined previously.

[0255] Where R²⁰ is —NR²⁶R²⁷, and R²⁶ and R²⁷ are as defined before, an amide compound is defined that can be used as a precursor intermediate and surprisingly as a MMP inhibitor compound. R²⁶ and R²⁷ are both preferably hydrido.

[0256] Where a R group is —NH—O—R¹⁴, and R¹⁴ is hydrido, or a pharmaceutically acceptable cation, an active hydroxamic acid or hydroxamate is defined. Where a R²⁰ group is —NH—O—R¹⁴, and R¹⁴ is a C(W)R²⁵ group as defined before, a pro-drug form of the hydroxamic acid is defined that can form a hydroxamic acid or hydroxamate form of the inhibitor in situ.

[0257] A particularly preferred precursor intermediate to an intermediate compound of formula VI is an intermediate compound of formula VII, below

[0258] wherein m, n, p, g, X, Z, Y, D and R²⁰ are as defined above for formula VI.

[0259] In regard to a compound of each of formulas VI and VII, the subscript letter “g” is used to show the oxidation state of the sulfur atom. Where g is zero, the sulfur is unoxidized, and the compound depicted is typically the sulfide reaction product of a sulfur-containing synthon as is illustrated in the examples hereinafter. Where g is 1, the sulfur is oxidized to a sulfoxide, whereas when g is 2, the sulfur is oxidized to a sulfone as is also illustrated hereinafter. A compound of formulas VI or VII wherein g is zero or 1 as itself typically an intermediate in the formation of a similar compound wherein g is 2 and the intermediate is a preferred sulfone.

[0260] A preferred intermediate corresponds in structure to formula VIIA, below, wherein R²⁰, X, Y, Z, m, n, p and D are as defined previously.

[0261] In the written descriptions of molecules and groups, molecular descriptors can be combined to produce words or phrases that describe structural groups or are combined to describe structural groups. Such descriptors are used in this document. Common illustrative examples include such terms as aralkyl (or arylalkyl), heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, aralkoxyalkoxycarbonyl and the like. A specific example of a compound encompassed with the latter descriptor aralkoxyalkoxycarbonyl is C₆H₅—CH₂—CH₂—O—CH₂—O—(C═O)— wherein C₆H₅— is phenyl. It is also to be noted that a structural group can have more than one descriptive word or phrase in the art, for example, heteroaryloxyalkylcarbonyl can also be termed heteroaryloxyalkanoyl. Such combinations are used herein in the description of the processes, compounds and compositions of this invention and further examples are described below. The following list is not intended to be exhaustive or drawn out but provide illustrative examples of words or phrases (terms) that are used herein.

[0262] As utilized herein, the term “alkyl”, alone or in combination, means a straight-chain or branched-chain alkyl radical containing 1 to about 12 carbon atoms, preferably 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.

[0263] The term “alkenyl”, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to about 12 carbon atoms preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like.

[0264] The term “alkynyl”, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing 2 to about 12 carbon atoms, preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.

[0265] The term “carbonyl” or “oxo”, alone or in combination, means a —C(═O)— group wherein the remaining two bonds (valences) can be independently substituted. The term carbonyl is also intended to encompass a hydrated carbonyl group —C(OH)₂—.

[0266] The term “thiol” or “sulfhydryl”, alone or in combination, means a —SH group. The term “thio” or “thia”, alone or in combination, means a thiaether group; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom.

[0267] The term “amino”, alone or in combination, means an amine or —NH₂ group whereas the term mono-substituted amino, alone or in combination, means a substituted amine —N(H)(substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted amine means a —N(substituent)₂ wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups.

[0268] Amines, amino groups and amides are compounds that can be designated as primary (I°), secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted or N,N-disubstituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (ammonium)(IV°) means a nitrogen with four substituents [—N⁺(substituent)₄] that is positively charged and accompanied by a counter ion, whereas N-oxide means one substituent is oxygen and the group is represented as [—N⁺(substituent)₃—O⁻]; i.e., the charges are internally compensated.

[0269] The term “cyano”, alone or in combination, means a —C-triple bond-N (—C≡N) group. The term “azido”, alone or in combination, means a —N-triple bond-N (—N≡N) group. The term “hydroxyl”, alone or in combination, means a —OH group. The term “nitro”, alone or in combination, means a —NO₂ group. The term “azo”, alone or in combination, means a —N═N-group wherein the bonds at the terminal positions can be independently substituted.

[0270] The term “hydrazino”, alone or in combination, means a —NH—NH— group wherein the depicted remaining two bonds (valences) can be independently substituted. The hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized.

[0271] The term “sulfonyl”, alone or in combination, means a —SO₂— group wherein the depicted remaining two bonds (valences) can be independently substituted. The term “sulfoxido”, alone or in combination, means a —SO— group wherein the remaining two bonds (valences) can be independently substituted.

[0272] The term “sulfone”, alone or in combination, means a —SO₂— group wherein the depicted remaining two bonds (valences) can be independently substituted. The term “sulfenamide”, alone or in combination, means a —SON═ group wherein the remaining three depicted bonds (valences) can be independently substituted. The term “sulfide”, alone or in combination, means a —S— group wherein the remaining two bonds (valences) can be independently substituted.

[0273] The term “alkoxy”, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

[0274] The term “cycloalkyl”, alone or in combination, means a cyclic alkyl radical that contains 3 to about 8 carbon atoms. The term “cycloalkylalkyl” means an alkyl radical as defined above that is substituted by a cycloalkyl radical containing 3 to about 8, preferably 3 to about 6, carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0275] A heterocyclic (heterocyclo) or heterocyclo portion of a heterocyclocarbonyl, heterocyclooxy-carbonyl, heterocycloalkoxycarbonyl, or heterocycloalkyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one or more hetero atoms selected from nitrogen, oxygen and sulphur. Heterocyclo compounds include benzofused heterocyclic compounds such as benzo-1,4-dioxane. Such a moiety can be optionally substituted on one or more ring carbon atoms by halogen, hydroxy, hydroxycarbonyl, alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom (i.e., —NH—) of the ring by alkyl, aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or on a tertiary nitrogen atom (i.e., ═N—) by oxido and that is attached via a carbon atom. The tertiary nitrogen atom with three substituents can also attached to form a N-oxide [═N(O)-] group.

[0276] The term “aryl”, alone or in combination, means a 5- or 6-membered carbocyclic aromatic ring-containing moiety or a fused ring system containing two or three rings that have all carbon atoms in the ring; i.e., a carbocyclic aryl radical. Exemplary carbocyclic aryl radicals include phenyl, indenyl and naphthyl radicals.

[0277] The term “heteroaryl”, alone or in combination means a 5- or 6-membered aromatic ring-containing moiety or a fused ring system (radical) containing two or three rings that have carbon atoms and also one or more heteroatoms in the ring(s) such as sulfur, oxygen and nitrogen. Examples of such heterocyclic or heteroaryl groups are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, and the like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, tetrazolyl, oxazolyl, oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, and the like), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, and the like), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolyl, and the like), 1,2,3,4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, and the like), quinoxalinyl, β-carbolinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl, and the like radicals.

[0278] When an aryl or heteroaryl radical is a substituting moiety (group, substituent, or radical), it can itself substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoro-methoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,

[0279] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino

[0280] wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group,

[0281] wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group

[0282] wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.

[0283] The term “aralkyl”, alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like.

[0284] The term “aralkoxycarbonyl”, alone or in combination, means a radical of the formula aralkyl-O—C(O)— in which the term “aralkyl” has the significance given above. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl.

[0285] The term “aryloxy” means a radical of the formula aryl-O— in which the term aryl has the significance given above. The phenoxy radical is an exemplary aryloxy radical.

[0286] The terms “heteroaralkyl” and “heteroaryloxy” mean radicals structurally similar to aralkyl and aryloxy that are formed from heteroaryl radicals. Exemplary radicals include 4-picolinyl and 2-pyrimidinoxy, respectively.

[0287] The terms “alkanoyl” or “alkylcarbonyl”, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include formyl, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.

[0288] The term “cycloalkylcarbonyl” means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid that is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.

[0289] The terms “aralkanoyl” or “aralkylcarbonyl” mean an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl and the like.

[0290] The terms “aroyl” or “arylcarbonyl” means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.

[0291] The term “cycloalkylalkoxycarbonyl” means an acyl group of the formula cycloalkylalkyl-O—CO— wherein cycloalkylalkyl has the significance given above. The term “aryloxyalkanoyl” means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term “heterocyclooxycarbonyl” means an acyl group having the formula heterocyclo-O—CO— wherein heterocyclo is as defined above.

[0292] The term “heterocycloalkanoyl” is an acyl radical of the formula heterocyclo-substituted alkane carboxylic acid wherein heterocyclo has the significance given above. The term “heterocycloalkoxycarbonyl” means an acyl radical of the formula heterocyclo-substituted alkane-O—CO— wherein heterocyclo has the significance given above. The term “heteroaryloxycarbonyl” means an acyl radical represented by the formula heteroaryl-O—CO— wherein heteroaryl has the significance given above.

[0293] The term “aminocarbonyl” (carboxamide) alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amine reacted with a carboxylic acid wherein the amino (amido nitrogen) group is unsubstituted (—NH₂) or a substituted primary or secondary amino group containing one or two substituents selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like, as recited. A hydroxamate is a N-hydroxycarboxamide.

[0294] The term “aminoalkanoyl” means an acyl group derived from an amino-substituted alkanecarboxylic acid wherein the amino group can be a primary or secondary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.

[0295] The term “halogen” means fluoride, chloride, bromide or iodide. The term “haloalkyl” means an alkyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.

[0296] The term “perfluoroalkyl” means an alkyl group wherein each hydrogen has been replaced by a fluorine atom. Examples of such perfluoroalkyl groups, in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.

[0297] The term “perfluoroalkoxy” alone or in combination, means a perfluoroalkyl ether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkoxy groups, in addition to trifluoromethoxy (F₃C—O—), are perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy and perfluorodecoxy.

[0298] The term “perfluoroalkylthio” alone or in combination, means a perfluoroalkyl thioether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkylthio groups, in addition to trifluoromethylthio (F₃C—S—), are perfluorobutylthio, perfluoroisopropylthio, perfluorododecylthio and perfluorodecylthio.

[0299] The term “aromatic ring” in combinations such as substituted-aromatic ring sulfone or substituted-aromatic ring sulfoxide means aryl or heteroaryl as defined before.

[0300] The term “pharmaceutically acceptable” is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product. Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.

[0301] “M” utilized in the reaction schemes that follow represents a leaving group such as halogen, phosphate ester or sulfate ester.

[0302] Preparation of Useful Compounds

[0303] Schemes A through C and Schemes 1 through 19 hereinbelow illustrate chemical processes and transformations that can be useful for the preparation of compounds useful in this invention; i.e., compounds of formulas I, II, III, IV and V and similar cyclic inhibitors. In addition, the preparation of compounds of formula VI and formula VII is illustrated. Compounds of formula VI and formula VII can be used as intermediates in the preparation of the compounds of formulas I, II, III, IV and V or pro-drugs or MMP inhibitors.

[0304] In Schemes A through C, the symbol J independently represents R²⁰ or other synthetically useful groups such as amides, acid chlorides, mixed anhydrides and the like. The n is 0, 1 or 2 and is preferred to be 1 or 2 in Scheme C. The n of these schemes corresponds to g in formulas VI and VII., and is zero, 1 or 2. The symbol m is 1 or 2. The symbol r is independently 1, 2 or 3. The symbol P represents a protecting group that can also be a member of the group R⁶. In Scheme A, for simplicity and clarity of illustration positional isomers are illustrated with a bond through the ring in standard fashion. Later Schemes typically only show one positional isomer but positional isomers are represented by these structures and reactions in a manner consistent with Formula I, II, III, IV, V, VI, VII above. Similarly, the symbol B represents O, S, SO, SO₂ and NR⁶. The symbols C and C′ independently are electrophilic groups or groups capable of participating in a condensation reaction. Here to it should be noted that the six-membered ring is shown for illustrative purposes but the procedures and/or reagents are applicable to and represent combinations the permit the preparation of 5- to 8-membered rings.

[0305] The structures in Schemes 1 through 19 are also shown with compounds that represent the other compounds of this invention. The aromatic ring in Scheme C is aryl and heteroaryl. The moieties of -A-R-E-Y are as defined before. Reactions illustrated involving a spiroheterocyclic nitrogen atom may not be applicable to those compounds with sulfur or oxygen.

[0306] Scheme A shows in step 1 the reduction of a heteraryl compound to a carboxyl derivative. Generally, the first product is a hydrogen-containing amine heterocycle when the starting material is aromatic or an R⁶-containing heterocycle when a partially unsaturated heterocycle is the starting material.

[0307] Compound 2 can be treated in several ways depending on the needs of the chemist. In Step 2, the nitrogen can be protected by preparing, for example, a carbobenzoxy (Z) or tert-butoxycarbonyl derivative. Such acylations can be carried out by methods well known in the art, especially the art of amino acid and peptide synthesis. The process of acylation with activated carboxyl group- or activated sulfonyl group-containing reagents to prepare contemplated compounds is carried out in the same manner. Examples of such acylating groups are carbonyl azides, halides, anhydrides, mixed anhydrides, carbodiimide derivatives or other less traditional activated ester groups such as the hydroxybenzotriazole derivative. These acylations can be run in the presence of base including mild bases such as triethylamine or N-ethylmorpholine if desired. The preparation of some activated ester reagents and their use to prepare other compounds useful in this invention is discussed below. It should be recalled that the groups constituting P and serving as a selectively removable protecting group can also be included as part of the group R⁶.

[0308] Step 4 of Scheme A shows the alkylation or acylation of Compound 2 to produce compound 5. The process of acylation and alkylation are as discussed herein. In Step 5, the group J can be changed if desired. An example of such a change is exchange of an ester for a THP-protected hydroxamate conversion of a THP-protected hydroxamate inot a hydroxamate or conversion of an acid into a protected hydroxamate or the like.

[0309] Steps 3, 7 and 8 show the preparation of sulfur-containing derivatives of the contemplated compounds or intermediates to those compounds. The starting material for the above steps (e.g., compounds 2, 5 and 6) can be treated with a base to deprotonate the carbon alpha to the carbonyl function. This anion can be reacted with a sulfur electrophile to produce a sulfone, sulfoxide or sulfide. Such electrophiles can be of the form of, for example, R²⁴S—SR²⁴, R²⁴SO₂C₁, R²⁴SC₁, R²⁴SOC₁, R²⁴S(O)—SR₂₄ and the like where R²⁴ is as defined before or is an aryl or heteroaryl sulfur-containing material containing a coupling substituent, R³′, that can be used to prepare one of the R²⁴-containing groups. Preparation of the anion requires a base and a strong base may be required such as one of the metal amides, hydrides or alkyls discussed herein. The solvents are nonprotic, and dipolar aprotic solvents are preferred along with an inert atmosphere. Subsequent schemes usually utilize R³ for the R²⁴ group for ease of illustration.

[0310] It should be noted that these processes produce sulfides (thio ethers), sulfoxides or sulfones depending on starting material. In addition, the sulfides can be oxidized to sulfoxides or sulfones, and the sulfoxides can be oxidized to their corresponding sulfone derivatives. The choice of position in the synthetic sequence to change the oxidation state of sulfur as well as the decision to change oxidation state is under the control of the chemist skilled in the art. Methods of oxidizing sulfur are discussed hereinbelow.

[0311] Scheme A, Steps 6, 9, 10 and 12 independently illustrate the interconversion of groups within J. Examples of such interconversions include exchange of an ester for hydroxamic acid or hydroxamic acid derivative, conversion of a carboxylic acid into an activated carbonyl derivative or into a hydroxamic acid or hydroxamic acid derivative (pro-drug or protected derivative), or removal of a protecting group from a hydroxamate derivative. The preparation of activated carbonyl compounds their reaction with nucleophiles such as hydroxamic acid, protected hydroxamates or hydroxamic acid pro-drugs is discussed below as is the conversion of protected hydroxamic acid derivatives into hydroxamic acids. The preparation of, for example, hydroxybenzotriazole/carbodiimide, derived products is discussed herein. The preparation or hydrolysis of esters, amides, amide derivatives, acid chlorides, acid anhydrides, mixed anhydrides and the like are synthetic methods very well known in the art, and are not discussed in detail herein. Step 6 illustrates the conversion of compound 4 into compound 9, without first being converted into compound 7.

[0312] Scheme B illustrates an alternate method of preparing contemplated compounds. The reagent shown above the arrow in Step 1 is a reagent with two active groups in addition to the heteroatoms (B) noted before. Here again, the particular reagent illustrated was selected to permit a clear illustration of the reaction, but it is also intended to represent reagents that permit the preparation of the heteroatom position, and 5-, 7- and 8-membered ring size compounds. These reagents are readily selected by those skilled in the art.

[0313] C and C′ in this Step 1 reagent are independently an electophile or a group convertible into an electrophile. Such groups include halides, sulfonic acid esters, epoxides, thioepoxides, hydroxyl groups, and the like. This reagent is reacted with a nucleophilic anion of a sulfur containing carbonyl compound such as compound 1. The anion is formed by deprotonation of compound 1 and examples of bases suitable for such a deprotonation are discussed below. Treatment with the above electrophilic reagent is carried out under alkylating conditions well known in the art and discussed herein. The product of this reaction can be either Compound 2 or Compound 3; i.e., the reaction can be carried out as a pot or two step process as required.

[0314] Step 3 illustrates the interconversion of J groups if desired as discussed above for Scheme A. Step 4 uses reagent where C, for example, represents a nucleophile as discussed above and C′ represents an electrophile or a nucleophile such as hydroxyl, thiol or R⁶-amino. It is noted that Cl can be, independently, a nucleophile or an electrophile when m is 2; i.e., the C′ groups are not required to be the same when m is 2. When m is 2, treatment with a second mole of base provides the skilled chemist an alternative preparation of Compound 5. When C′ is hydroxyl, thiol, or R⁶-amino and m is 2, the person skilled in the art can condense Compound 4 with, for example, an aldehyde or ketone, under reductive conditions or with subsequent reduction to form a contemplated compound. As above, the compound where m is 2 can be made in one step (one pot process) or two steps, thus permitting the chemist the choice of having the reagent(s) be the same (one pot) or different (two step).

[0315] Scheme B also illustrates the interconversions of the groups within J, the oxidation state of the sulfur and groups on nitrogen; i.e., R⁶ groups, to provide the contemplated compounds. These methods and processes are discussed above for the reactions of Scheme A.

[0316] Scheme C illustrates the nucleophilic displacement of a group D as defined herein. This reaction is carried out in a similar manner to the displacement reactions discussed herein. The choice of oxidation state of the sulfur is made by the person skilled in the art, but sulfoxide or sulfone groups are preferred, and the sulfone is most preferred. The displacement can be carried out either before or after the methylene next to the carbonyl group is reacted to form a Spiro heterocyclic group.

[0317] Steps 1, 2 and 3 also illustrate that although the nucleophilic displacement can be carried out with one nucleophile (Nu), the product of this reaction can be modified by methods well known in the art and as shown herein to provide the group -A-R-E-Y as defined hereinbefore.

[0318] A non-limiting illustration of such a process is provided when D is fluoride. The fluoride leaving group can be directly displaced with the anion of 4-trifluoromethylphenol, 4-trifluoromethoxyphenol, 4-trifluoromethylthiophenol and the like to provide a contemplated compound. This is a one pot process from Compound 4. Other compounds included in -A-R-E-Y can be prepared by displacing the fluoride leaving group with ammonia to provide an amine, which can then be acylated by methods discussed wherein with, for example, 4-trifluoromethylbenzoyl chloride, to form another contemplated product compound.

[0319] The R⁶ function can be changed and/or further modified in compounds or at steps in the Schemes as desired or required by the person skilled in the art to prepare the contemplated compounds. Interconversion of dual purpose functional groups such as short or long term protecting groups into other R⁶ groups has been mentioned. Many other routine and/or useful conversions, including the preparation of synthetic intermediates, are very well known in the art. A few non-limiting examples of such conversions or reactions include: reductions; nucleophilic displacement/substitution reactions; exchange or preparation of carboxylic or sulfonic acids, amides, esters, acid halides, mixed anhydrides and the like; electrophilic displacement/substitution reactions; oxidations; ring/chain conversions, ring opening reactions, condensation reactions including those involving sulfonyl or carbonyl groups and/or carbon-hydrogen bonds influenced by either or both of those groups. The selection of preparative methods or conversion methods of the contemplated compounds and the order of the reaction(s) is made by the skilled person. It is expected that should a particular sequence or method prove to be undesirable that an alternative will be selected and used. Included is the choice of preparing/adding the groups in a single step using a convergent inhibitor strategy or preparing the final R⁶ group following a stepwise strategy.

[0320] Thus, in general, the choices of starting material and reaction conditions can vary as is well known to those skilled in the art. Usually, no single set of conditions is limiting because variations can be applied as required. Conditions are also selected as desired to suit a specific purpose such as small scale preparations or large scale preparations. In either case, the use of less safe or less environmentally sound materials or reagents is usually be minimized. Examples of such materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, chloroform, benzene and the like.

[0321] These reactions can be carried out under a dry inert atmosphere such a nitrogen or argon if desired. Selected reactions known to those skilled in the art, can be carried out under a dry atmosphere such as dry air whereas other synthetic steps, for example, aqueous acid or base ester or amide hydrolysis, can be carried out under laboratory air. In addition, some processes of these syntheses can be carried out in a pressure apparatus at pressures above, equal to or below atmospheric pressure. The use of such an apparatus aids in the control of gaseous reagents such as hydrogen, ammonia, trimethylamine, methylamine, oxygen and the like, and can also help prevent the leakage of air or humidity into a reaction in progress. This discussion is not intended to be exhaustive as it is readily noted that additional or alternative methods, conditions, reactions or systems can be identified and used by a chemist of ordinary skill.

[0322] The illustrated reactions are usually carried out at a temperature of between −25° C. to solvent reflux under an inert atmosphere such as nitrogen or argon. The solvent or solvent mixture can vary widely depending upon reagents and other conditions and can include polar or dipolar aprotic solvents as listed or mixtures of these solvents. Reactions can be carried out at lower temperatures such as dry ice/acetone or liquid nitrogen temperature if desired to carry out such reactions as metalations or anion formations using strong bases.

[0323] In some cases, amines such as triethylamine, pyridine or other non-reactive bases can serve as reagents and/or solvents and/or co-solvents. In some instances, in these reactions and other reactions in these Schemes, protecting groups can be used to maintain or retain groups in other parts of a molecule(s) at locations that is(are) not desired reactive centers. Examples of such groups that the skilled person can maintain or retain include, amines, other hydroxyls, thiols, acids and the like. Such protecting groups can include acyl groups, arylalkyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups, silyl groups including trisubstituted silyl groups, ester groups and the like. Examples of such protecting groups include acetyl, trifluoroacetyl, tetrahydropyran (THP), benzyl, tert-butoxy carbonyl (BOC or TBOC), benzyloxycarbonyl (Z or CBZ), tert-butyldimethylsilyl (TBDMS) or methoxyethoxymethylene (MEM) groups. The preparation of such protected compounds as well as their removal is well known in the art. The protecting groups can also be used as substituents in the contemplated compounds whose utility is as a drug rather than as a synthetic intermediate.

[0324] Many reactions or processes involve bases that can act as reactants, reagents, deprotonating agents, acid scavengers, salt forming reagents, solvents, co-solvents and the like. Bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium, cesium or magnesium hydroxide, oxides such as those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, cesium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, primary (I°), secondary (II°) or tertiary (III°) organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides. As non-limiting examples, such amines can include triethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N,N′-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine, and the like. Non-limiting examples of ammonium hydroxides, usually made from amines and water, can include ammonium hydroxide, triethylammonium hydroxide, trimethylammonium hydroxide, methyldiiospropylammonium hydroxide, tribenzylammonium hydroxide, dimethylbenzylammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N,N′-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limiting examples, quaternary ammonium hydroxides can include tetraethylammonium hydroxide, tetramethylammonium hydroxide, dimethyldiiospropyl-ammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclononylammonium hydroxide, methyltribenzylammonium hydroxide, N,N-dimethyl-morpholiniumhydroxide, N,N,N′,N′-tetramethylpiperazinium hydroxide, and N-ethyl-N′-hexylpiperidinium hydroxide and the like.

[0325] Metal hydrides, amides or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, aluminum hydride, diisobutylaluminum hydride (DIBAL) sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like can also be suitable reagents. Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl lithium, phenyl lithium, tert-butyl lithium, lithium acetylide or butyl lithium, Grignard reagents such as methylmagnesium bromide or methymagnesium chloride, organocadmium reagents such as dimethylcadmium and the like can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents. Pharmaceutically acceptable bases can be reacted with acids to form contemplated pharmaceutically acceptable salts. It should also be noted that optically active bases can be used to make optically active salts which can be used for optical resolutions.

[0326] Generally, reaction media can comprise a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system. The solvents can be protic, non-protic or dipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like. Typical non-protic solvents include acetone, tetrahydrofuran (THF), dioxane, diethyl ether, tert-butylmethyl ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like. Dipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, DMSO, hexamethylphosphorus triamide (HMPA), nitromethane, tetramethylurea, N-methylpyrrolidone and the like. Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides or thiols for making contemplated products and the like.

[0327] The preparation of compounds contemplated herein can require the oxidation of nitrogen or sulfur to N-oxide derivatives or sulfoxides or sulfones. Reagents for this process can include, in a non-limiting example, peroxymonosulfate (OXONE®), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hypochlorite, sodium hydpochlorite, hypochlorous acid, sodium meta-periodate, periodic acid and the like with the weaker agents being most useful for the preparation of sulfones and sulfoxides. Protic, non-protic, dipolar aprotic solvents, either pure or mixed, can be chosen, for example, methanol/water.

[0328] The oxidation can be carried out at temperature of about −780 to about 50° degrees Centigrade, and normally selected from a range −10° C. to about 40° C. Sulfoxides are best prepared using one equivalent of oxidizing agent. It can be desirable in the case of more active oxidizing agents, but not required, that the reactions be carried out under an inert gas atmosphere with or without degassed solvents. It should be noted that the oxidation of sulfides to sulfones can be carried out in one step or two steps via the sulfoxide as desired by the chemist.

[0329] Reduction is a well known process in the art with a useful method being hydrogenation. In such cases (catalytic reduction), there can be a metal catalyst such as Rh, Pd, Pt, Ni or the like with or without an additional support such as carbon, barium carbonate and the like. Solvents can be protic or non-protic pure solvents or mixed solvents as required. The reductions can be carried out at atmospheric pressure to a pressure of multiple atmospheres with atmospheric pressure to about 40 pounds per square inch (psi) preferred or very high pressures in special hydrogenation equipment well known in the art.

[0330] Reductive alkylation of amines or active methylene compounds is also a useful method of preparing compounds. Such alkylations can be carried out under reductive hydrogenation conditions as presented above using, for example, aldehydes or ketones. Hydride transfer reagents such as sodium cyanoborohydride, aluminum hydride, lithium aluminumhydride, borane, sodium borohydride, di-isobutylaluminum hydride and the like are also useful as reagents for reductive alkylation. Acyl groups can be reduced in a similar manner to produce substituted amines.

[0331] Alternative methods of alkylating carbon or nitrogen are direct alkylation. Such an alkylation, as is well known in the art, can be carried by treatment of an activated carbon containing at least one hydrogen with base to form the corresponding anion, adding an electrophilic reagent and permitting the SN2 reaction to proceed. An amine to be alkylated is treated similarly except that deprotonation may not be required. Electrophiles include halogen derivatives, sulfonate esters, epoxides and the like.

[0332] Bases and solvents for alkylation reactions are those discussed above. Preferred are bases that are hindered such that competition with the electrophile is minimized. Additional preferred bases are metal hydrides, amide anions or organometallic bases such as n-butyl lithium. The solvents, solvent mixtures or solvent/reagent mixtures discussed are satisfactory but non-protic or dipolar aprotic solvents such as acetone, acetonitrile, DMF and the like are examples of preferred classes.

[0333] Acids are used in many reactions during various syntheses. For example, removal of the THP protecting group to produce the hydroxamic acid. The acid can be a mono-, di- or tri-protic organic or inorganic acid. Examples of acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorus acid, p-toluene sulfonic acid, trifluoromethane sulfonic acid, trifluoroacetic acid, difluoroacetic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, 2,6-dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, and the like. They can also be Lewis acids such as aluminum chloride, borontrifluoride, antimony pentafluoride and the like. Acids in a protic can also be used to hydrolyze esters, amides and the like as well as catalyze exchange reactions.

[0334] Conversion of a carboxylic acid protected as an ester or amide into a hydroxamic acid or hydroxamic acid derivative such as an O-arylalkylether or O-cycloalkoxyalkylether group is useful. In the case where hydroxylamine is used, treatment of an ester or amide with one or more equivalents of hydroxylamine hydrochloride at room temperature or above in a solvent or solvents, usually protic or partially protic, such as those listed above can provide a hydroxamic acid directly. This exchange process can be further catalyzed by the addition of additional acid. Alternatively, a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol, can be used to form hydroxylamine from hydroxylamine hydrochloride in situ which can exchange with an ester or amide. As mentioned above, exchange can be carried out with a protected hydroxylamine such as tetrahydropyranylhydroxyamine (THPONH₂), benzylhydroxylamine (BnONH₂), and the like in which case compounds such as shown in Schemes A, B and C that are tetrahydropyranyl (THP) or benzyl (Bn) hydroxamic acid derivatives are the products. Removal of the protecting groups when desired, for example, following further transformations in another part of the molecule or following storage, is accomplished by standard methods well known in the art such as acid hydrolysis of the THP group as discussed above or reductive removal of the benzyl group with hydrogen and a metal catalyst such as palladium, platinum, palladium on carbon or nickel.

[0335] In the case where R²⁰ is hydroxyl; i.e., where the intermediate is a carboxylic acid, standard coupling reactions can be used. For example, the acid can be converted into an acid chloride, mixed anhydride or activated ester such as hydroxybenzotriazole and treated with hydroxylamine or a protected hydroxylamine in the presence of a non-competitive base to the nitrogen acylated compound. This is the same product as discussed above. Couplings of this nature are well known in the art and especially the art related to peptide and amino acid chemistry.

[0336] An amide of this invention, whether used as a drug or as a protecting group, is prepared by treatment of an acid halide, anhydride, mixed anhydride or active ester with a primary amine, secondary amine or ammonia, or their equivalent. These standard coupling reactions are well known in the art and are discussed elsewhere herein. An alternative method of preparation of amides is by the exchange of, for example, an alkoxycarbonyl (ester) or aminecarbonyl (amide) group for an amine or different amine as required. Ester exchange processes are especially useful when less hindered amines, including ammonia, are used to make the corresponding amides of this invention.

[0337] Further, amides can be prepared from hydroxamic acids or protected hydroxamic acid compounds by catalytic reductions or in vivo or in vitro enzymatic processes. For example, catalytic reduction of O-benzylhydroxamic acid compounds is known to produce varying ratios of amide and hydroxamic acid depending upon the catalyst used as well as other reaction conditions such as solvent, temperature, hydrogen gas pressure and the like.

[0338] Compounds contemplated herein can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, enantiomers, diastereoisomers, as well as in the form of racemic or nonracemic mixtures. A compound can also exist in other isomeric forms such as ortho, meta and para isomers, cis and trans isomers, syn and anti isomers, E and Z isomers, tautomeric isomers, alpha and beta isomers, axial and equatorial isomers and isomers due to hindered rotation. An isomer can exist in equilibrium with another isomer in a mammal or a test system. Such a compound can also exist as an isomeric equilibrium system with a solvent or water, for example, as a hydrated ketone or aldehyde, as is well known in the art. All isomers are included as compounds of this invention.

[0339] The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, are applicable to the preparation of the corresponding compounds that are contemplated.

[0340] Table 1 through Table 165, below, show several contemplated aromatic sulfone hydroxamic acid inhibitor compounds or structural formulas that illustrate substituent groups. Each group of compounds is illustrated by a generic formula, or formulae, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position clearly shown in the generic structure. The substituent symbols, e.g., R1 and R2 and R3, are as shown in each Table, and are typically not those used before. One or two bonds (wavy lines) are shown with those substituents to indicate the respective positions of attachment in the illustrated compound. This system is well known in the chemical communication arts and is widely used in scientific papers and presentations. For example in Table 2, R1 and R2 together with the atoms to which they are bonded is the variable group with the structural entities that can substitute for R1 and R2 together shown in the balance of that table. TABLE 1

1

7

2

8

3

9

4

10 

5

11 

6

12 

[0341] TABLE 2 II

1

2

3

4

5

6

7

8

9

10 

11 

12 

[0342] TABLE 3

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0343] TABLE 4

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0344] TABLE 5

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0345] TABLE 6

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0346] TABLE 7

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0347] TABLE 8

1

2

3

4

5

6

7

8

9

10 

11 

[0348] TABLE 9

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0349] TABLE 10

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0350] TABLE 11

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0351] TABLE 12

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0352] TABLE 13

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0353] TABLE 14

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0354] TABLE 15

1

2

3

4

5

6

7

8

9

10

11

[0355] TABLE 16

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0356] TABLE 17

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

[0357] TABLE 18

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0358] TABLE 19

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0359] TABLE 20

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0360] TABLE 21

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0361] TABLE 22

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

[0362] TABLE 23

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0363] TABLE 24

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0364] TABLE 25

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0365] TABLE 26

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0366] TABLE 27

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0367] TABLE 28

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0368] TABLE 29

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

[0369] TABLE 30

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0370] TABLE 31

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0371] TABLE 32

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0372] TABLE 33

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0373] TABLE 34

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0374] TABLE 35

1

2

3

4

5

6

7

8

9

10 

11 

[0375] TABLE 36

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0376] TABLE 37

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0377] TABLE 38

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0378] TABLE 39

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0379] TABLE 40

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0380] TABLE 41

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0381] TABLE 42

1

2

3

4

5

6

7

8

9

10 

11 

[0382] TABLE 43

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0383] TABLE 44

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0384] TABLE 45

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0385] TABLE 46

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0386] TABLE 47

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0387] TABLE 48

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0388] TABLE 49

1

2

3

4

5

6

7

8

9

10 

11 

[0389] TABLE 50

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0390] TABLE 51

[0391] TABLE 52

[0392] TABLE 53

[0393] TABLE 54

[0394] TABLE 55

[0395] TABLE 56

[0396] TABLE 57

[0397] TABLE 58

[0398] TABLE 59

[0399] TABLE 60

[0400] TABLE 61

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0401] TABLE 62

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0402] TABLE 63

1

2

3

4

5

6

7

8

9

10

11

[0403] TABLE 64

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0404] TABLE 65

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

[0405] TABLE 66

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0406] TABLE 67

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0407] TABLE 68

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0408] TABLE 69

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0409] TABLE 70

1

2

3

4

5

6

7

8

9

10

11

[0410] TABLE 71

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0411] TABLE 72

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0412] TABLE 73

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0413] TABLE 74

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0414] TABLE 75

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0415] TABLE 76

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0416] TABLE 77

1

2

3

4

5

6

7

8

9

10 

11 

[0417] TABLE 78

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0418] TABLE 79

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0419] TABLE 80

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0420] TABLE 81

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0421] TABLE 82

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0422] TABLE 83

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0423] TABLE 84

1

2

3

4

5

6

7

8

9

10 

11 

[0424] TABLE 85

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0425] TABLE 86

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0426] TABLE 87

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0427] TABLE 88

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0428] TABLE 89

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0429] TABLE 90

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0430] TABLE 91

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

[0431] TABLE 92

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0432] TABLE 93

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0433] TABLE 94

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0434] TABLE 95

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0435] TABLE 96

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0436] TABLE 97

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0437] TABLE 98

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

[0438] TABLE 99

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0439] TABLE 100

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0440] TABLE 101

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0441] TABLE 102

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0442] TABLE 103

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0443] TABLE 104

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0444] TABLE 105

1

2

3

4

5

6

7

8

9

10

11

[0445] TABLE 106

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0446] TABLE 107

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

[0447] TABLE 108

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

[0448] TABLE 109

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0449] TABLE 110

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0450] TABLE 111

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0451] TABLE 112

1

2

3

4

5

6

7

8

9

10 

11 

[0452] TABLE 113

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0453] TABLE 114

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0454] TABLE 115

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0455] TABLE 116

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0456] TABLE 117

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0457] TABLE 118

1

2

3

4

5

6

7

8

9

10 

11 

[0458] TABLE 119

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0459] TABLE 120

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

[0460] TABLE 121

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0461] TABLE 122

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0462] TABLE 123

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

[0463] TABLE 124

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0464] TABLE 125

1

2

3

4

5

6

7

8

9

10 

11 

[0465] TABLE 126

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0466] TABLE 127

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0467] TABLE 128

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

[0468] TABLE 129

1

14

2

15

3

16

4

17

5

18

6

19

7

20

8

21

9

22

10 

23

11 

24

12 

25

13 

26

[0469] TABLE 130

1

14

2

15

3

16

4

17

5

18

6

19

7

20

8

21

9

22

10 

23

11 

24

12 

25

13 

26

[0470] TABLE 131

1

14

2

15

3

16

4

17

5

18

6

19

7

20

8

21

9

22

10

23

11

24

12

25

13

26

[0471] TABLE 132

1

14

2

15

3

16

4

17

5

18

6

19

7

20

8

21

9

22

10

23

11

24

12

25

13

26

[0472] TABLE 133

1

14

2

15

3

16

4

17

5

18

6

19

7

20

8

21

9

22

10

23

11

24

12

25

13

26

[0473] TABLE 134

1

14

2

15

3

16

4

17

5

18

6

19

7

20

8

21

9

22

10

23

11

24

12

25

13

26

[0474] TABLE 135

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0475] TABLE 136

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0476] TABLE 137

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0477] TABLE 138

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0478] TABLE 139

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0479] TABLE 140

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0480] TABLE 141

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0481] TABLE 142

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0482] TABLE 143

1

2

3

4

5

6

7

8

9

10

11

12

[0483] TABLE 144

1

2

3

4

5

6

7

8

9

10

11

12

[0484] TABLE 145

1

2

3

4

5

6

7

8

9

10

11

12

[0485] TABLE 146

1

2

3

4

5

6

7

8

9

10

11

12

[0486] TABLE 147

1

2

3

4

5

6

7

8

9

10

11

12

[0487] TABLE 148

1

2

3

4

5

6

7

8

9

10

11

12

[0488] TABLE 149

1

2

3

4

5

6

7

8

9

10

11

12

[0489] TABLE 150

1

2

3

4

5

6

7

8

9

10

11

12

[0490] TABLE 151

 1

22

 2

23

 3

24

 4

25

 5

26

 6

27

 7

28

 8

29

 9

30

10

31

11

32

12

33

13

34

14

35

15

36

16

37

17

38

18

39

19

40

20

41

21

42

[0491] TABLE 152

43

70

44

71

45

72

46

73

47

74

48

75

49

76

50

78

51

79

52

80

53

81

54

82

55

83

56

84

57

85

58

86

59

87

60

88

61

89

62

90

63

91

64

92

65

93

66

94

67

95

68

96

69

[0492] TABLE 153

 97

112

 98

113

 99

114

100

115

101

116

102

117

103

118

104

119

105

120

106

121

107

122

108

123

109

124

110

125

111

126

[0493] TABLE 154

127

142

128

143

129

144

130

145

131

146

132

147

133

148

134

149

135

150

136

151

137

152

138

153

139

154

140

155

141

156

[0494] TABLE 155

157

165

158

166

159

167

160

168

161

169

162

170

163

171

164

172

[0495] TABLE 156

 1

22

 2

23

 3

24

 4

25

 5

26

 6

27

 7

28

 8

29

 9

30

10

31

11

32

12

33

13

34

14

35

15

36

16

37

17

38

18

39

19

40

20

41

21

42

[0496] TABLE 157

43

70

44

71

45

72

46

73

47

74

48

75

49

76

50

78

51

79

52

80

53

81

54

82

55

83

56

84

57

85

58

86

59

87

60

88

61

89

62

90

63

91

64

92

65

93

66

94

67

95

68

96

69

[0497] TABLE 158

 97

112

 98

113

 99

114

100

115

101

116

102

117

103

118

104

119

105

120

106

121

107

122

108

123

109

124

110

125

111

126

[0498] TABLE 159

127

142

128

143

129

144

130

145

131

146

132

147

133

148

134

149

135

150

136

151

137

152

138

153

139

154

140

155

141

156

[0499] TABLE 160

157

165

158

166

159

167

160

168

161

169

162

170

163

171

164

172

[0500] TABLE 161

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

[0501] TABLE 162

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

78

79

80

81

82

83

84

85

86

87

88

89

95

90

91

92

93

94

96

[0502] TABLE 163

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

[0503] TABLE 164

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

[0504] TABLE 165

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

[0505] Treatment Method

[0506] A contemplated inhibitor compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity.

[0507] Also contemplated is use of a contemplated metalloprotease inhibitor compound in the treatment of a disease state that can be affected by the activity of metalloproteases TNF-α convertase. Exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.

[0508] In treating a disease condition associated with pathological matrix metalloproteinase activity, a contemplated MMP inhibitor compound can be used in the form of an amine salt derived from an inorganic or organic acid. Exemplary salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.

[0509] Also, a basic nitrogen-containing group can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility. Water or oil-soluble or dispersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid.

[0510] Other compounds useful in this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.

[0511] In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.

[0512] Total daily dose administered to a host mammal in single or divided doses can be in amounts, for example, for 0.001 to 30 mg/kg body weight daily and more usually 0.01 to 10 mg. Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. A suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should this be desired by the person prescribing the drug.

[0513] The dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.

[0514] A compound of the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.

[0515] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.

[0516] Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

[0517] Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, a contemplated aromatic sulfone hydroximate inhibitor compound can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.

[0518] For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from soerile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. A contemplated aromatic sulfone hydroximate inhibitor compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

[0519] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

[0520] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.

BEST MODE FOR CARRYING OUT THE INVENTION

[0521] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the remainder of the disclosure in any way whatsoever.

[0522] Abbreviations are often used for reagents and solvents in the specific examples that follow. Those abbreviations and their meanings are as follows:

[0523] BOC=t-butoxycarbonyl

[0524] DEAD=diethyl azodicarboxylate

[0525] DMF=dimethylformamide

[0526] DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

[0527] EtOAc=ethyl acetate

[0528] EDC=1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride

[0529] Et₂O=diethyl ether

[0530] HOBT=1-hydroxybenzotriazole

[0531] MeOH=methanol

[0532] MeCl₂=methylene chloride

[0533] MsCl=methanesulfonyl chloride

[0534] NMM=N-methyl morpholine

[0535] THF=tetrahydrofruan

[0536] TsCl=toluenesulfonyl chloride

[0537] THP—O-hydroxylamine=O-tetrahydropyran-hydroxylamine and O-tetrahydro-2H-pyran-2-yl-hydroxylamine

[0538] The preparation of compounds useful in the synthesis of compounds of the invention are provided herein below in Preparative Examples I through XI.

PREPARATIVE EXAMPLE I Preparation of 1,1-dimethylethyl ester 4-[(hydroxyamino)-carbonyl]-4-[(phenoxyphenyl)-sulfonyl]-1-piperidinecarboxylic acid

[0539]

[0540] Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (DMSO; 20 mL) was heated to sixty-five degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H₂O and saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).

[0541] Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 minutes. The solution was stirred overnight (about eighteen hours) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (7:3 ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound (26.2 g, quantitative yield) as a clear, colorless oil.

[0542] Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol in THF (30 mL), cooled to minus seventy-eight degrees Celsius, was added n-butyl lithium (12.5 mL, 20 mmol) drop-wise. After 15 minutes, the BOC-piperidine compound of part B (2.6 g, 10 mmol) in THF (10 mL) was added drop-wise. After 1.5 hours the solution was cooled to minus sixty degrees Celsius and the disulfide of part A (2.0 g, 10 mmol) in THF (7 mL). The solution was stirred at ambient temperature for 2 hours. The solution was diluted with H₂O and extracted with ethyl acetate. The organic layer was washed with H₂O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as an oil (1.8 g, 40%).

[0543] Part D: To a solution of the sulfide of part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to zero degrees Celsius, was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hours followed by dilution with H₂O and extraction with dichloromethane. The organic layer was washed with 10 percent Na₂SO₄, H₂O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).

[0544] Part E: To a solution of the sulfone of part D (800 mg, 1.63 mmol) in THF (9 mL) and ethanol (9 mL) was added NaOH (654 mg, 16.3 mmol) in H₂O (3 mL). The solution was heated at sixty-five degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in H₂O. Following acidification with 2N HCl to pH 4, the solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the acid as a white foam (790 mg, quantitative yield). Analytical calculated for C₂₃H₂₇NO₇S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.59.

[0545] Part F: To a solution of the acid of part G (730-mg, 1.58 mmol) in DMF (9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424 mg, 2.21 mmol), 4-methylmorpholine (0.521 mL, 4.7 mmol) and 50 percent aqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20 hours and additional N-hydroxybenzotriazole.H₂O (256 mg), EDC (424 mg) and 50 percent aqueous hydroxylamine (1.04 mL) were added. After an additional 24 hours of stirring the solution was diluted with H₂O and extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (on silica, acetonitrile/H₂O) provided the title compound as a white solid (460 mg, 61%). HPLC purity: >99%. Analytical calculated for C₂₃H₂₈N₂O₇S: C, 57.97; H, 5.92; N, 5.88; S, 6.73. Found: C, 57.95; H, 6.02; N, 5.81; S, 6.85.

PREPARATIVE EXAMPLE II Preparation of N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride

[0546]

[0547] Part A: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 minutes. The solution was stirred overnight (about eighteen hours) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield).

[0548] Part B: A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in DMSO (500 mL) was heated to 65 degrees Celsius for 6 hours. The reaction was quenched into wet ice and the resulting solid was collected by vacuum filtration to provide the disulfide as a white solid (34.4 g, 68.9%).

[0549] Part C: To a solution of the BOC-piperdine compound of part A (16 g, 62 mmol) in THF (300 mL) cooled to minus 50 degrees Celsius was added lithium diisopropylamide (41.33 mL, 74 mmol) and the solution was stirred for 1.5 hours at zero degrees Celsius. To this solution was added the disulfide of part B (15.77 g, 62 mmol), and the resulting solution was stirred at ambient temperature for 20 hours. The reaction was quenched with the addition of H₂O and the solution was concentrated in vacuo. The aqueous residue was extracted with ethyl acetate and the organic layer was washed with 0.5N KOH, H₂O, and saturated NaCl. Chromatography (on silica, hexane/ethyl acetate) provided the sulfide as an oil (18.0 g, 75%).

[0550] Part D: To a solution of the sulfide of part C (16.5 g, 43 mmol) in dichloromethane (500 mL) cooled to zero degrees Celsius was added 3-chloroperbenzoic acid (18.0 g, 86 mmol) and the solution was stirred for 20 hours. The solution was diluted with H₂O and extracted with dichloromethane. The organic layer was washed with 10 percent Na₂SO₃, H₂O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (10.7 g, 60%).

[0551] Part E: Into a solution of the sulfone of part D (10 g, 24.0 mmol) in ethyl acetate (250 mL) was bubbled HCl gas for 10 minutes followed by stirring at ambient temperature for 4 hours. Concentration in vacuo provided the amine hydrochloride salt as a white solid (7.27 g, 86%).

[0552] Part F: To a solution of the amine hydrochloride salt of part E (5.98 g, 17.0 mmol) in DMF (120 mL) was added potassium carbonate (4.7 g, 34.0 mmol) followed by propargyl bromide (2.02 g, 17.0 mmol) and the solution was stirred for 4 hours at ambient temperature. The solution was partitioned between ethyl acetate and H₂O, and the organic layer was washed with H₂O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a yellow oil (5.2 g, 86%).

[0553] Part G: To a solution of the propargyl amine of part F in DMF (15 mL) was added thiophenol (0.80 mL, 7.78 mmol) and CsCO₃ (2.79 g, 8.56 mmol) and the solution was heated to 70 degrees Celsius for 6 hours. The solution was partitioned between ethyl ether and H₂O. The organic layer was washed with H₂O and saturated NaCl, and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the S-phenoxyphenyl compound as an oil (1.95 g, 56%).

[0554] Part H: To a solution of the S-phenoxyphenyl of part G (1.81 g, 4.06 mmol) in ethanol (21 mL) and H₂O (3.5 mL) was added KOH (1.37 g, 24.5 mmol) and the solution was heated to 105 degrees Celsius for 4.5 hours. The solution was acidified to a pH value of 1 with concentrated HCl solution and then concentrated to provide the acid as a yellow residue that was used without additional purification (1.82 g).

[0555] Part I: To a solution of the acid of part H (1.82 g, 4.06 mmol) in acetonitrile (20 mL) was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine (723 mg, 6.17 mmol) and triethylamine (0.67 mL, 4.86 mmol). To this stirring solution was added EDC (1.18 g, 6.17 mmol) and the solution was stirred for 18 hours. The solution was partitioned between H₂O and ethyl acetate. The organic layer was washed with H₂O, saturated NaHCO₃ and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as a white solid (1.32 g, 63%).

[0556] Part J: To a solution of the protected hydroxamate of part I (9.65 g, 18.7 mmol) in methanol (148 mL) cooled to zero degrees Celsius was added acetyl chloride (4.0 mL, 56.2 mmol), and the solution was stirred for 45 minutes at ambient temperature. Concentration in vacuo followed by trituration with ethyl ether provided the title compound as a white solid (8.10 g, 94%). MS(CI) MH⁺ calculated for C₂₁H₂₂N₂O₄S₂: 431, found 431.

PREPARATIVE EXAMPLE III Preparation of N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride

[0557]

[0558] Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated to 65 degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H₂O and saturated NaCl, and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).

[0559] Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) dropwise over 20 minutes. The solution was stirred overnight at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexane) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield).

[0560] Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL), cooled to minus seventy-eight degrees Celsius, was added n-butyl lithium (12.5 mL, 20 mmol) dropwise. After 15 minutes, the BOC-piperidine compound of Part B (2.6 g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 hours, the solution was cooled to minus sixty degrees Celsius and the disulfide of Part A (2.0 g, 10 mmol) in THF (7 mL) was added. The solution was stirred at ambient temperature for 2 hours. The solution was diluted with H₂O and extracted with ethyl acetate. The organic layer was washed with H₂O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as an oil (1.8 g, 40%).

[0561] Part D: To a solution of the sulfide of

[0562] Part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to zero degrees Celsius, was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hours followed by dilution with H₂O and extraction with dichloromethane. The organic layer was washed with 10 percent Na₂SO₄, H₂O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).

[0563] Part E: Into a solution of the sulfone of

[0564] Part D (3.56 g, 7.0 mmol) in ethyl acetate (100 mL) cooled to zero degrees Celsius was bubbled HCl gas for 5 minutes. Concentration in vacuo followed by trituration with ethyl ether provided the amine hydrochloride salt as a white solid (3.5 g, quantitative yield). MS(CI) MH⁺ calculated for C₂₀H₂₃NO₅S: 390, found 390.

[0565] Part F: To a solution of the amine hydrochloride salt of part E (2.6 g, 6 mmol) and K₂CO₃ (1.66 g, 12 mmol) in DMF (50 mL) was added propargyl bromide (892 mg, 6 mmol) and the solution was stirred at ambient temperature for 4 hours. The solution was diluted with H₂O and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a white solid (2.15 g, 82%).

[0566] Part G: To a solution of the propargyl amine of part F (2.15 g, 5 mmol) in THF (30 mL) and ethanol (30 mL) was added NaOH (2.0 g, 50 mmol) and the solution was heated at 65 degrees Celsius for 48 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to a pH value of 5. Vacuum filtration of the resulting precipitate provided the acid as a white solid (2.04 g, quantitative yield).

[0567] Part H: To a solution of the acid of part G (559 mg, 1.4 mmol) in dichloromethane (5 mL) was added triethylamine (0.585 mL, 4.2 mmol) and 50 percent aqueous hydroxylamine (0.925 mL, 14.0 mmol) followed by bromotris(pyrrolidino)phosphonium hexafluourphosphate (PyBroP; 718 mg, 1.54 mmol). The solution was stirred at ambient temperature for 4 hours. The solution was diluted with H₂O and extracted with dichloromethane. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (on silica, acetonitrile/H₂O) provided the hydroxamate as a white solid (140 mg, 25%). Analytical calculation for C₂₁H₂₂N₂O₅S: C, 60.85; H, 5.37; N, 6.76; S, 7.74. Found: C, 60.47; H, 5.35; N, 6.61; S, 7.46.

[0568] Part I: To a solution of the hydroxamate of part H (121 mg, 0.292 mmol) in methanol (2 mL) cooled to zero degrees Celsius was added acetyl chloride (0.228 mL, 0.321 mmol) in methanol (1 mL). After stirring at ambient temperature for 30 minutes the solution was concentrated under a stream of N₂. Trituration with ethyl ether provided the title compound as a white solid (107 mg, 81%). Analytical calculation for C₂₁H₂₂N₂O₅S.HCl.0.3H₂O: C, 55.27; H, 5.21; N, 6.14. Found: C, 54.90; H, 5.37; N, 6.07.

PREPARATIVE EXAMPLE IV Preparation of 4-[(4-fluorophenyl)sulfonyl]tetrahydro-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide

[0569]

[0570] Part A: In dry equipment under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at two degrees Celsius. The reaction was stirred at ambient temperature for forty five minutes at which time the sodium had dissolved. The solution was chilled to five degrees Celsius and p-fluorothiophenol (41.55 mL, 0.39 mmol) was added, followed by methyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction was stirred at ambient temperature for four hours, filtered, and concentrated in vacuo to give the sulfide as a clear colorless oil (75.85 g, 97%).

[0571] Part B: To a solution of the sulfide from part A (75.85 g, 0.38 mol) in methanol (1000 mL) were added water (100 mL) and Oxone (720 g, 1.17 mol) at 20 degrees Celsius. An exotherm to 67 degrees Celsius was noted. After two hours, the reaction was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo to give the sulfone as a crystalline solid (82.74 g, 94%).

[0572] Part C: To a solution of the sulfone from part B (28.5 g, 0.123 mol) in N,N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g, 0.27 mol), bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol), and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction was stirred overnight (about 18 hours) at ambient temperature. The reaction was slowly poured into 1N HCl (300 mL), the resultant solid filtered and the cake washed well with hexanes. The solid was recrystallized from ethyl acetate/hexanes to give the pyran compound as a beige solid (28.74 g, 77%). MS (ES+) MH+ calculated for C₁₃H₁₅O₅S₁F₁: 303, found 303.

[0573] Part D: In dry equipment under nitrogen, the pyran compound from part C (8.0 g, 26.5 mmol) was dissolved in dry tetrahydrofuran (250 mL) and a solution of potassium trimethylsilonate (10.2 g, 79.5 mmol) in dry tetrahydrofuran (15 mL) was added at ambient temperature. After ninety minutes, water (100 mL) was added and the solution concentrated in vacuo. The residue was taken up in water and extracted with ethyl acetate to remove unreacted starting material. The aqueous solution was treated with 6N HCl until pH=1. The slurry was extracted with ethyl acetate and the combined extracts washed with water, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was heated in diethyl ether, the solid filtered and dried to give the carboxylic acid as a crystalline solid (5.78 g, 76%). HRMS (ES−) M-H calculated for C₁₂H₁₃O₅ S₁F₁: 287.04, found 287.04.

[0574] Part E: In dry equipment under nitrogen, the carboxylic acid from part D (9.1 g, 31.6 mmol) was dissolved in dry N,N-dimethylformamide (70 mL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (5.1 g, 37.9 mmol), N-methylmorpholine (10.4 mL, 94.8 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (11.5 g, 98 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.48 g, 44.2 mmol). After three hours at ambient temperature, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO₄, saturated NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the title compound as a crystalline solid (9.7 g, 80%). HRMS (ES+) MH+ calculated for C₁₇H₂₂NO₆ S₁F₁: 388.12, found 388.12.

PREPARATIVE EXAMPLE V Preparation of tetrahydro-N-hydroxy-4-[[4-[4-trifluoromethoxy)-phenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide

[0575]

[0576] Part A: To a solution of the title compound of Preparative Example IV (3.1 g, 8 mmol) in N,N-dimethylacetamide (20 mL) were added cesium carbonate (8.8 g, 27 mmol) and p-(trifluoromethoxy)phenol (2.1 mL, 16 mmol). The slurry was stirred at 95 degrees Celsius for nineteen hours. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the substituted THP-protected hydroxamate as a white foam (4.2 g, 96%). HRMS (ES+) MH+ calculated for C₂₄H₂₆N₁O₈S₁F₃: 546.14, found 546.14.

[0577] Part B: To a slurry of the THP-protected hydroxamate from part A (4.0 g, 7.3 mmol) in dioxane (20 mL) were added a 4N HCl dioxane solution (20 mL) and methanol (20 mL). After fifteen minutes at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na₂SO₄, filtered, and concentrated in vacuo. The product was recrystallized (acetone/hexanes) to give the title compound as a white solid (2.2 g, 65%). HRMS (ES+) M+NH₄ ⁺ calculated for C₁₉H₁₈N₁O₇S₁F₃: 479.11, found 479.11.

PREPARATIVE EXAMPLE VI Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-(2-phenoxy-ethoxy)phenyl]sulfonyl]-4-piperidine carboxamide, monohydrochloride

[0578]

[0579] Part A: To a solution of the product of Preparative Example II, part E, (14.36 g, 40 mmol) in methanol (50 mL) was added acetic acid (24.5 g, 400 mmol), a portion (about 2 g) of 4-Angstrom molecular sieves, (1-ethoxycyclopropyl)-oxytrimethyl silane (25.8 mL, 148 mmol) and sodium cyanoborohydride (7.05 g, 112 mmol). The solution was heated at reflux for 8 hours. The precipitated solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H₂O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO₄, filtered and concentrated in vacuo. The solid was filtered, washed with H₂O/diethyl ether to give the desired cyclopropyl amine {ethyl 4-[(4-fluorophenyl-sulfonyl)]-1-cyclopropyl-4-piperidinecarboxylate} as a white solid (11.83 g, 81.5%). MS MH³⁰ calculated for C₁₇H₂₂NO₄SF: 356, found: 356.

[0580] Part B: A solution of the cyclopropyl amine of Part A (2.0 g, 5.6 mmol), ethylene glycol phenyl ether (2.8 mL, 23 mmol), and cesium carbonate (7.3 g, 23 mmol) in DMAC (10 mL) was heat at 125-135 degrees Celsius for 18 hours under an atmosphere of nitrogen. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, dissolved in diethyl ether, precipitated as the hydrochloride salt, and dried at 40 degrees Celsius in a vacuum oven. The solid was dissolved into a mixture of water, acetonitrile, and ethanol and then the pH was adjusted to 12 with 1N NaOH solution. The mixture was concentrated in vacuo to remove ethanol and acetonitrile. The solid was isolated by filtration, washed with water, and dried at 50 degrees Celsius in a vacuum oven to afford the ether as a white solid (1.8 g, 68%): MS+ calcd. for C₂₅H₃₁NO₆S 474, found 474. Anal. calcd. for C₂₅H₃₁NO₆S: C, 63.40; H, 6.60; N, 2.96; S, 6.77. Found: C, 63.35; H, 6.59; N, 2.99; S, 6.61.

[0581] Part C: A mixture of the ether of part B (1.8 g, 3.7 mmol) and a 50% NaOH aqueous solution (3.0 g, 37 mmol) in THF (32 mL), EtOH (32 mL), and H₂O (16 mL) was heated at 60 degrees Celsius under a nitrogen atmosphere for 24 hours. The material was concentrated in vacuo and triturated with diethyl ether to give a solid. The tan solid was dissolved into a mixture of water, ethanol, and THF, precipitated by adjusting the pH to 3 with concentrated hydrochloric acid, concentrated in vacuo, triturated with water, and dried at 50 degrees Celsius in a vacuum oven to give a crude white solid acid (2.3 g).

[0582] A mixture of the crude white solid acid (2.3 g), N-hydroxybenzotriazole (1.9 g, 14 mmol), 4-methylmorpholine (1.6 mL, 14 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.1 g, 9.4 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.7 g, 14 mmol) in DMF (90 mL) was stirred at ambient temperature under a nitrogen atmosphere for 2 days. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was washed with 1N NaOH solution, water, and brine, dried over magnesium sulfate, concentrated in vacuo, and purification by flash chromatography (20:80 to 40:60 ethyl acetate/toluene) to afford the protected hydroxamate as a white solid: (0.43 g, 21%): MS MH+ calcd. for C₂₈H₃₆N₂O₇S 545, found 545. Anal. calcd. for C₂₈H₃₆N₂O₇S: C, 61.74; H, 6.66; N, 5.14; S, 5.89. Found: C, 61.72; H, 6.75; N, 5.06; S, 5.91.

[0583] Additional compound was isolated by acidifying the aqueous layer to pH of 3, collecting the solid by filtration, and drying to give a white solid (0.80 g).

[0584] Part D: To an ambient temperature solution of acetyl chloride (0.31 mL, 4.4 mmol) in methanol (11 mL) under a nitrogen atmosphere was added the protected hydroxamate of part C (0.80 g, 1.5 mmol). After stirring for 2.5 hours, the precipitate was collected by filtration, washed with diethyl ether, and dried at 45 degrees Celsius in a vacuum oven to afford the title compound as a white solid (0.58 g, 79%): MS MH+ calcd. for C₂₃H₂₈N₂O₆S 461, found 461. Anal. calcd. for C₂₃H₂₈N₂O₆S.1.5 HCl: C, 53.62; H, 5.77; N, 5.44; S, 6.22. Found: C, 53.47; H, 5.79; N, 5.41; S, 6.16.

PREPARATIVE EXAMPLE VII Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0585]

[0586] Part A: To a solution of the product of Preparative Example II, Part D (30 g, 161 mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K₂CO₃ (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added 2-bromoethyl methyl ether (19 mL, 201 mmol), and solution was stirred at ambient temperature for 36 hours. Then, N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over MgSO₄. Concentration in vacuo provided the methoxyethyl amine as a light yellow gel (26.03 g, 86.8%).

[0587] Part B: To a solution of methoxyethyl amine (6.0 g, 16.0 mmol) of Part A and powdered K₂CO₃ (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H₂O and dried over MgSO₄. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).

[0588] Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of Part B (7.81 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147 mmol) in H₂O (28 mL) from an addition funnel at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH=2. Vacuum filtration of white precipitation provided the acid as a white solid (5.64 g, 73.3%).

[0589] Part D: To a solution of the acid of Part C (5.64 g, 10.8 mmol), N-methyl morpholine (4.8 mL, 43.1 mmol), 1-hydroxybenzotriazole (4.38 g, 32.4 mmol) and O-tetrahydropyranyl hydroxylamine (2.5 g, 21.6 mmol) in N,N-dimethylformamide (50 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.2 g, 32.4 mmol), and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO₃, H₂O and dried over MgSO₄. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl-protected hydroxamate as a white foam (6.65 g, quantitative yield).

[0590] Part E: To a solution of 4N HCl in dioxane (28 mL, 110 mmol) was added a solution of the tetrahydropyranyl-protected hydroxamate of Part D (6.65 g, 11.03 mmol) in methanol (3 mL) and dioxane (9 mL) and was stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether provided the title compound as a white solid (4.79 g, 78.2%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃.HCl.0.5H₂O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.

PREPARATIVE EXAMPLE VIII Preparation of N-hydroxy-1-[2-(4-morpholinyl)-ethyl]-4-[[4-[4-(trifluoromethyl)phenoxy]-phenyl] sulfonyl]-4-piperidinecarboxamide, dihydrochloride

[0591]

[0592] Part A: To a suspension of 4-bromopiperidine hydrobromide (107.0 g, 0.436 mol) in tetrahydrofuran (1 L) was slowly added triethylamine (122 mL, 0.872 mol) followed by di-tert-butyl dicarbonate (100 g, 0.458 mol), which was added in several portions. The resulting mixture was stirred at ambient temperature for 22 hours then filtered and concentrated in vacuo. The solids were washed with hexanes and then collected by filtration to give the Boc-piperidine compound as an amber oil (124 g, >100%).

[0593] Part B: To a solution of 4-fluorophenol (50.0 g, 0.390 mol) in acetone (400 mL), degassed with N₂, was added Cs₂CO₃ (159 g, 0.488 mol). After degassing the resulting mixture with N₂ for 5 minutes, the Boc-piperidine compound of Part A (85.9 g, 0.325 mol) was added. The resulting mixture was stirred at ambient temperature for 18 hours and then filtered through a pad of Celite®, washing with acetone. The filtrate was concentrated in vacuo to provide the sulfide as a tan residue (98.5 g, 97%).

[0594] Part C: To a solution of the sulfide of Part B (8.00 g, 25.7 mmol) in dichloromethane (90 mL) and methanol (15 mL) was added monoperoxyphthalic acid magnesium salt hexahydrate (19.1 g, 38.6 mmol) in two portions. The resulting mixture was stirred at ambient temperature for 1.5 hours and then filtered. The filtrate was washed with saturated NaHCO₃ and then with saturated NaCl. The combined aqueous layers were extracted with dichloromethane (100 mL). The combined organic layers were dried over Na₂SO₄ and then concentrated in vacuo. The resulting solids were washed with hexanes then dissolved in dichloromethane and filtered through a pad of Celite®, washing with dichloromethane. The filtrate was concentrated in vacuo and recrystallization from ethyl acetate provided the sulfone as a white crystalline solid (4.45 g, 50%).

[0595] Part D: To a solution of sulfone of Part C (7.00 g, 20.4 mmol) in N,N-dimethylformamide (40 mL) was added Cs₂CO₃ (19.9 g, 61.2 mmol) and α,α,α-trifluoro-α-cresol (3.97 g, 24.5 mmol). The resulting mixture was heated at eighty degrees Celsius for 16 hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuo. The resulting residue was treated with H₂O and the solids were collected by filtration. The solids were then washed with hexanes then methanol to provide the biaryl ether as a tan solid (8.60 g, 87%).

[0596] Part E: To a solution of the biaryl ether of Part D (8.59 g, 17.7 mmol) in tetrahydrofuran (100 mL), cooled to zero degrees Celsius, was slowly added lithium bis(trimethylsilyl)amide (22.0 mL, 1.0M in tetrahydrofuran, 22.0 mmol), at such a rate that the temperature of the reaction never exceeded one degree Celsius. The resulting mixture was stirred at zero degrees Celsius for 1 hour then a solution of methyl chloroformate (2.05 mL, 26.6 mmol) in tetrahydrofuran (5.0 mL) was slowly added, at such a rate that the temperature of the reaction mixture never exceeded four degrees Celsius. After the addition was complete, the mixture was slowly permitted to warm to ambient temperature. Saturated NH₄Cl (50 mL) was added and the tetrahydrofuran was removed in vacuo. Water (50 mL) was added to the residue which was then extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over Na₂SO₄. Recrystallization from methanol provided the methyl ester as a pale yellow crystalline solid (7.66 g, 80%).

[0597] Part F: To a solution of the methyl ester of Part E (7.66 g, 14.1 mmol) in dioxane (30 mL) and methanol (10 mL) was added a solution of 4N HCl in dioxane (10 mL, 40 mmol). After stirring at ambient temperature for 2 hours additional 4N HCl in dioxane (10 mL, 40 mmol) was added. After stirring at ambient temperature for 2.5 hours, the reaction mixture was concentrated in vacuo to provide the amine as an off-white solid (6.80 g, >100%).

[0598] Part G: To a suspension of the amine of Part F (3.00 g, 6.25 mmol) in acetonitrile (20 mL) was added K₂CO₃ (3.46 g, 25.0 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.22 g, 6.56 mmol) and a catalytic amount of NaI. The resulting mixture was heated at reflux for 22 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo to provide the morpholinyl ethyl amine as a tan solid (3.45 g, >100%).

[0599] Part H: To a solution of the morpholinyl ethyl amine of Part G (3.45 g, 6.25 mmol) in tetrahydrofuran (60 mL) was added potassium trimethylsilanolate (1.60 g, 12.50 mmol). After stirring at ambient temperature for 25 hours, H₂O was added. The reaction mixture was then neutralized (pH 7) with 1N HCl. The tetrahydrofuran was removed in vacuo and the resulting precipitate was collected by filtration and washed with diethyl ether to provide the amino acid as an off-white solid (2.87 g, 85%).

[0600] Part I: To a suspension of the amino acid of

[0601] Part H (2.87 g, 5.29 mmol) in dichloromethane (25 mL) was added N-methylmorpholine (1.74 mL, 15.9 mmol), 0-(tetrahydropuranyl) hydroxylamine (0.682 g, 5.82 mmol) and PyBroP® (2.96 g, 6.35 mmol). After stirring at ambient temperature for 19 hours additional N-methylmorpholine (0.872 mL, 7.94 mmol), O-(tetrahydropuranyl) hydroxylamine (0.310 g, 2.65 mmol) and PyBroP® (1.48 g, 3.17 mmol) were added. The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H₂O. The organic layers were washed with saturated NaCl and dried over Na₂SO₄. Chromatography (on silica, methanol/chloroform) provided the protected hydroxamate as an off-white solid (2.62 g, 77%).

[0602] Part J: To a solution of the protected hydroxamate of Part I (2.62 g, 4.08 mmol) in dioxane (9 mL) and methanol (3 mL) was added a solution of 4N HCl in dioxane (10 mL, 40.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hours and then diethyl ether (20 mL) was added. The resulting solids were collected by filtration to give the title compound as an off-white solid (2.31 g, 90%). MS MH⁺ calculated for C₂₅H₃₁O₆N₃SF₃: 558, found 558.

PREPARATIVE EXAMPLE IX Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride

[0603]

[0604] Part A: To a solution of the product of Preparative Example VI, Part A, (6.97 g, 19.6 mmol) in DMF (500 mL) was added K₂CO₃ (3.42 g, 18.0 mmol) and 4-(triflouromethoxy)phenol (3.7 g, 24.8 mmol). The solution was stirred at ninety degrees Celsius for 40 hours. The solution was diluted with H₂O (600 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO₄, filtered and concentrated in vacuo to afford the desired diaryl ether as an oil (8.5 g, quantitative). HRMS MH⁺ calculated for C₂₄H₂₆NSO₆F₃: 514.1511. Found 514.1524.

[0605] Part B: To a solution of diaryl ether from Part A (8.4 g, 16.4 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (6.54 g, 164 mmol) in water (20 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo to remove most of organic solvents and the aqueous residue was acidified to pH=4.0. The resulting precipitate was filtered to give the desired filtered to give the hydrochloride salt as a white solid (5.01 g, 63%). HRMS MH⁺ calculated for C₂₂H₂₂NSO₆F₃: 486.1198, found 486.1200.

[0606] Part C: To a solution of the hydrochloride salt of Part B (5.0 g, 10.3 mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (1.65 g, 12.3 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (1.8 g, 15.4 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.60 g, 12.3 mmol). The solution was stirred at ambient temperature for 42 hours. The solution was diluted with H₂O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO₄, filtered and concentrated in vacuo. Chromatography on silica gel, eluting with 30% ethyl acetate/hexane provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (5.41 g, 89%).

[0607] Part D: To a solution of tetrahydropyranyl-protected hydroxamate of Part C (5.4 g, 9.2 mmol) in dioxane (80 mL) and methanol (20 mL) was added 4 N HCl/dioxane (50 mL). The reaction was stirred at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (4.02 g, 81%). HRMS MH⁺ calculated for C₂₂H₂₃N₂SO₆F₃: 501.1307, found 501.1324.

PREPARATIVE EXAMPLE X Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethyl) phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0608]

[0609] Part A: To a solution of the product of Preparative Example VI, Part A, (5.96 g, 15.0 mmol) in DMF (100 mL) was added K₂CO₃ (12.34 g, 38.0 mmol) and α,α,α-trifluoromethyl phenol (3.65 g, 22.5 mmol). The solution was stirred ninety degrees Celsius for 28 hours. The solution was diluted with H₂O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO₄, filtered and concentrated in vacuo to afford desired aryl ether as an oil (7.54 g, quantitative)

[0610] Part B: To a solution of aryl ether from Part A (7.54 g, 15.0 mmol) in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (6.06 g, 151.0 mmol) in water (20 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2.0. The resulting precipitate was filtered to give the desired hydrochloride salt as a white solid (7.98 g, quantitative). MS MH⁺ calculated for C₂₂H₂₂NSO₅F₃: 470, found 470.

[0611] Part C: To a solution of the hydrochloride salt of Part B (7.60 g, 15.0 mmol) in DMF (100 mL) were added 1-hydroxybenzotriazole (2.44 g, 18.0 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (2.63 g, 22.5 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.02 g, 21.0 mmol). The solution was stirred at ambient temperature for 96 hours. The solution was diluted with H₂O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO₄, filtered and concentrated in vacuo. Chromatography on silica eluting with 30% ethyl acetate/hexane provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (5.93 g, 69%).

[0612] Part D: To a solution of tetrahydropyranyl-protected hydroxamate of Part C (3.8 g, 6.7 mmol) in dioxane (100 mL) was added 4 N HCl/dioxane (30 mL). The reaction was stirred at ambient temperature for 2 hours, then the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (3.33 g, 96%). MS MH⁺ calculated for C₂₂H₂₃N₂SO₅F₃: 485, found 485.

PREPARATIVE EXAMPLE XI Preparation of Resin II

[0613] Step 1: Attachment of Compound of

PREPARATIVE EXAMPLE IV TO RESIN I

[0614] A 500 mL round-bottomed flask was charged with of resin I [Floyd et al., Tetrahedron Lett. 1996, 37, 8045-8048] (8.08 g, 9.7 mmol) and 1-methyl-2-pyrrolidinone (50 mL). A magnetic stirring bar was added, and the resin slurry slowly stirred. A separate solution of the compound of Part D, Preparative Example IV (5.58 g, 19.4 mmol) in 1-methyl-2-pyrrolidinone (35 mL) was added to the slurry followed by addition of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (10.1 g, 19.4 mmol) in one portion. Once the hexafluorophosphate salt had dissolved, 4-methylmorpholine (4.26 mL, 39 mmol) was added dropwise. The reaction slurry was stirred at room temperature for 24 hours, then the resin was collected in a sintered-disc funnel and washed with N,N-dimethylformamide, methanol, methylene chloride and diethyl ether (3×30 mL each solvent). The resin was dried in vacuo to yield 10.99 g polymer-bound hydroxymate as a tan polymeric solid. Theoretical loading on polymer was 0.91 mmol/g. FTIR microscopy showed bands at 1693 and 3326 cm⁻¹ indicative of the hydroxamate carbonyl and nitrogen-hydrogen stretches, respectively.

[0615] Step 2: Preparation of Resin III:

[0616] Reaction of Resin II With Nucleophiles

[0617] Resin II (50 mg, 0.046 mmol) was weighed into an 8 mL glass vial, and a 0.5 M solution of a nucleophile in 1-methyl-2-pyrrolidinone (1 mL) was added to the vessel. In the case of phenol and thiophenol nucleophiles, cesium carbonate (148 mg, 0.46 mmol) was added, and in the case of substituted piperazine nucleophiles, potassium carbonate (64 mg, 0.46 mmol) was added. The vial was capped and heated to 70 to 155 degrees Celsius for 24-48 hours, then cooled to room temperature. The resin was drained and washed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone/water (1:1), water, 10% acetic acid/water, methanol, and methylene chloride (3×3 mL each solvent).

[0618] Large Scale Preparation of Resin IIIa:

[0619] Resin II (5 g, 0.91 mmol) was weighed into an oven-dried three-necked round bottom flask fitted with a temperature probe, an overhead stirring paddle, and a nitrogen inlet. Anhydrous 1-methyl-2-pyrrolidinone (35 mL) was added to the flask followed by ethyl isonipecotate (7.0 mL, 45.5 mmol). The resin slurry was stirred slowly with the overhead stirrer, and the mixture was heated to 80 degrees Celsius with a heating mantle for 65 hours. The flask was thereafter cooled to room temperature.

[0620] The resin was collected in a sintered-disk glass funnel and washed with N,N-dimethylformamide, methanol and methylene chloride (3×30 mL each solvent). The resin was dried in vacuo to provide 5.86 g of resin IIIa as off-white resin beads. The theoretical loading of the polymer was 0.81 mmol/g. TFA cleavage performed on 50 mg of resin IIIa as described in step 3 yielded 10.4 mg of off-white solid spectroscopically indistinguishable from a known sample.

[0621] Step 3: Cleavage of Hydroxamic Acids From The Polymer-Support

[0622] Resin III was treated with a trifluoroacetic acid/water mixture (19:1, 1 mL) for 1 hour at room temperature. During that time, the resin became a deep red color. The resin was then drained and washed with trifluoroacetic acid/water (19:1) and methylene chloride (2×1 mL each solvent), collecting the combined filtrates in a tared vial. The volatiles were removed in vacuo, then a toluene/methylene chloride mixture (2 mL each) was added to the residue. The mixture was again concentrated in vacuo. The product was characterized by electrospray mass spectroscopy.

[0623] Step 4: Hydrolysis of Polymer-Bound Ester: Preparation of Resin IVa

[0624] Resin IIIa (5.8 g, 4.5 mmol) was weighed into a three-necked round bottomed flask fitted with an overhead stirring paddle. 1,4-Dioxane was added to the flask, and the resin slurry was stirred for 15 minutes. Then, a 4 M solution of KOH (5 mL, 20 mmol) was added, and the mixture was stirred for 44 hours. The resin was thereafter collected in a sintered-disk glass funnel and washed with dioxane/water (9:1), water, 10% acetic acid/water, methanol and methylene chloride (3×30 mL each solvent). The resin was dried in vacuo to yield 5.64 g of resin IVa as off-white polymer beads. FTIR microscopy showed bands at 1732 and 1704 cm⁻¹ and a broad band from 2500-3500 cm⁻¹. The theoretical loading of the polymer-bound acid was 0.84 mmol/g.

EXAMPLE 1 Preparation of 1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy) phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide

[0625]

[0626] Part A: To a solution of the product of Preparative Example II, part D, (30 g, 161 mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K₂CO₃ (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added 2-bromoethyl methyl ether (19 mL, 201 mmol) and solution was stirred at ambient temperature for 36 hours. Then N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over MgSO₄. Concentration in vacuo provided the methoxyethyl amine as a light yellow gel (26.03 g, 86.8%).

[0627] Part B: To a solution of the methoxyethyl amine (6.0 g, 16.0 mmol) of part A and powdered K₂CO₃ (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H₂O and dried over MgSO₄. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).

[0628] Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of part B (7.81 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147 mmol) in H₂O (28 mL) from an addition funnel at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH=2. Vacuum filtration of the white precipitation provided the carboxylic acid as a white solid (5.64 g, 73.3%).

[0629] Part D: To a suspension of the carboxylic acid of part C (200 mg, 0.397 mmol) in methylene chloride (4 mL) was added oxalyl chloride (101 mg, 0.80 mmol). After 15 minutes at ambient temperature the volatiles were removed under vacuum. The solid residue was resuspended in methylene chloride (4 mL) and gaseous ammonia was bubbled through the suspension. Triethylamine (81 mg, 0.80 mmol) was added and the stream of ammonia gas through the reaction was continued for 1 minute. Concentration afforded a solid which was chromatographed (reverse phase C₁₈ silica eluting with a gradient of 30% acetonitrile/water to 100% acetonitrile) to afford the desired primary amide as a colorless powder (6 mg, 3 mg). MS MH⁺ calculated for C₂₂H₂₅N₂ F₃O₆S: 503, found 503. HRMS M+ calculated for C₂₂H₂₅N₂ F₃O₆S: 503.1464, found 503.1472.

EXAMPLE 2 Preparation of 4-[(4-phenylthiophenyl) sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide

[0630]

[0631] A mixture of the acid from Preparative Example II, part H, (1.29 g, 2.85 mMol), N-hydroxybenzotriazole (1.15 g, 8.54 mMol), 4-methylmorpholine (0.94 mL, 14 mMol), concentrated NH₄OH (3 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.64 g, 8.54 mMol) in DMF (25 mL) was stirred at ambient temperature for 20 hours. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO₃, water, and brine, dried over magnesium sulfate, and concentrated in vacuo. Chromatography (on silica, MeOH/CHCl₃) afford the title amide as a white solid (0.143 g, 12%). Analytical calculation for C₂₁H₂₂N₂O₃S₂: C, 60.84; H, 5.35; N, 6.76; S, 15.47. Found: C, 60.74; H, 5.31; N, 6.74; S, 15.43.

EXAMPLES 3-58

[0632] The following compounds were prepared by parallel synthesis (resin based synthesis, automated synthesis) using parallel synthesis from Resin IVa as described previously in Preparative Example XI the following compounds were prepared:

MS Example Amine R (M + H) 3 3,5-Dimethylpiperidine

508 4 N-Methylpropargylamine

464 5 N-Methylallylamine

466 6 1-(1-phenylethyl)- piperazine

585 7 1-(2-phenylethyl)- piperazine

585 8 1-(2-chlorophenyl)- piperazine

591 9 1-(4-methoxyphenyl)-2- methylpiperazine

585 10 1-(5-Chloro-2- methylphenyl)piperazine

605 11 1-(2-methoxyphenyl)- piperazine

587 12 1-Acetylpiperazine

523 13 1-(2,4-Dimethylphenyl)- piperazine

585 14 N-(2-hydroxyethyl)- piperazine

525 15 1-(Ethoxy- carbonylmethyl)- piperazine

567 16 1-(2-Fluorophenyl)- piperazine

575 17 1-(2-Furoyl)-piperazine

575 18 1-(Cyclopentyl)- piperazine

549 19 1-(2-Propyl)-piperazine

523 20 N-(2-(1-Piperazino)- acetyl)pyrrolidine

592 21 1-(3-Dimethyl- aminopropyl)- piperazine

566 22 1-(2-Methoxyethyl)- piperazine

539 23 1-(2-Dimethyl- aminoethyl)- piperazine

552 24 1-(2-Ethoxyphenyl)- piperazine

601 25 1-(4-Fluorphenyl)- piperazine

575 26 1-(2-Pyridyl)-piperazine

558 27 2-(1-piperazinyl)- pyrimidine

559 28 4-Piperazino- acetophenone

599 29 1-(4-Nitrophenyl)- piperazine

602 30 1-(3,5-Dichloropyrid-4- yl)piperazine

626 31 4-(2-Methoxyphenyl)- piperidine

586 32 N-[2-Nitro-4- (trifluoromethyl)- phenyl]piperazine

670 33 1-[3-(Trifluormethyl)- pyrid-2-yl]- piperazine

626 34 cis-3,5-Dimethyl- morpholine

510 35 N-Propylcyclopropane- methylamine

508 36 1-(2,4-Difluorphenyl)- piperazine

593 37 1-(4-Pyridyl)- piperazine

558 38 1-(4-Trifluoromethyl- phenyl)-piperazine

625 39 1-Allylpiperazine

521 40 1-(2-Pyrazinyl)- piperazine

559 41 1-[3-Chloro-5- (trifluoromethyl)pyrid- 2-yl)]piperazine

660 42 1-(2-(4-Morpholino)- ethyl)piperazine

594 43 3-Chlorophenyl- piperazine

591 44 4-(Hydroxymethyl)- piperidine

510 45 Diisobutylamine

524 46 cis-2,6-Dimethyl- piperazine

509 47 3-Methylpiperidine

494 48 N,N-Diallylamine

492 49 1-[4-(Trifluormethyl)- 2-pyrimidyl]- piperazine

627 50 1-[4-(Trifluormethyl)- 2-pyridyl]- piperazine

626 51 N,N,N′-Trimethyl- ethylenediamine

497 52 (4-Ethylaminomethyl)- pyridine

531 53 Methyl-cyclopropylamine

466 54 3,5-Dimethyl-piperidine

508 55 3,5-Dimethyl-piperidine

508 56 Isobutylamine

468 57 Propylamine

454 58 N-Methyl- isobutylamine

482

EXAMPLES 59-78

[0633] Step 5: Preparation of Resin V

[0634] Into a fritted reaction vessel was weighed resin IVa (100 mg, 0.083 mmol), and the vessel was capped under nitrogen and cooled to zero degrees Celsius. A 1.0 M solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine in methylene chloride (0.4 mL, 0.4 mmol) was added followed by a 1.0 M solution of N-methylmorpholine in methylene chloride (0.6 mL, 0.6 mmol.) The solutions were stirred for 4 hours at zero degrees Celsius and warmed to ambient temperature. A 0.7 M solution of the appropriate amine to be reacted in methylene chloride (0.4 mL, 0.28 mmol) was added and the reaction mixture stirred for 24 hours. The reaction mixture was stirred for 24 hours, then the resin was drained and washed with 1-methyl-2-pyrrolidinone and methylene chloride (4×3 mL each solvent). The reaction was repeated using the same amounts of reagents described above. The reaction was stirred for 4 hours at zero degrees Celsius after the activating step and ambient temperature for 24 hours following amine solution addition. After 24 hours, the resin was drained and washed with 1-methyl-2-pyrrolidinone, 1:1 1-methyl-2-pyrrolidinone/water, water, 1:9 acetic acid/water, methanol and methylene chloride (3×3 mL each solvent).

[0635] The following hydroxamic acids were synthesized using the indicated polymer-bound acid and the indicated amine in Step 5 followed by release from the polymer using Step 3, before:

Example Amine R MS (M + H) 59 Aniline

488 60 N-Methylaniline

502 61 4-(Trifluoromethyl)- aniline

556 62 4-Aminopyridine

489 63 2-(Trifluoromethoxy)- aniline

572 64 2-Chloroaniline

522 65 2-Fluoroaniline

506 66 o-Anisole

518 67 2-(Methylamino)- pyridine

503 68 3-(Trifluoromethoxy)- aniline

572 69 3-(Trifluoromethyl)- aniline

556 70 3-Chloroaniline

522 71 3-Fluoroaniline

506 72 m-Anisole

518 73 4-(Trifluoromethoxy)- aniline

572 74 4-Aminopyrmidine

490 75 4-Fluoroaniline

506 76 p-Anisole

518 77 N,N-Dimethyl-1,3- phenylenediamine

531 78 N,N-Dimethyl-p- phenylenediamine

531

EXAMPLES 79-88

[0636] Step 12: Further Synthesis of Resin III.

[0637] Into a 8 mL glass vial was placed resin II (200 mg, 0.18 mmol) and cesium carbonate (0.98 g mg, 3 mmol) (no cesium carbonate used with piperidine and pyrrolidine nucleophiles). One mL of a 1.8 M solution of the amine nucleophile to be reacted in 1-methyl-2-pyrrolidinone (1.8 mmol) was added and the vial was capped and heated to 100 degrees Celsius for 30 hours. Then the vessel was cooled to room temperature, and the resin was drained and washed with 1-methyl-2-pyrrolidinone, 1:1 1-methyl-2-pyrrolidinone/water, water, 1:9 acetic acid/water, methanol and methylene chloride (3×3 mL each solvent).

[0638] The following hydroxamic acids were synthesized from Resin III using Step 11 with the indicated amines, followed by release from the polymer using the reaction conditions in Step 3.

Example Amine R MS (M + H) 79 1-(2-Methoxyphenyl)- piperidine

475 80 4-(4-Methoxybenzoyl)- piperidine

503 81 Pyrrolidine

355 82 1-(4-Methoxyphenyl)-2- piperazine

490 83 1-(2-Fluorophenyl)- piperazine

464 84 1-(2,4- Diemthylphenyl)- piperiazine

474 85 1-(2-Methoxyphenyl- piperazine

476 86 1-(4-Trifluoromethyl- phenyl)piperazine

514 87 1-(2,4- Difluorophenyl)- piperazine

482 88 1-(2-Chlorphenyl)- piperazine

480

EXAMPLE 89 Preparation of N-hydroxy-4 [[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(9-fluorenylmethoxy-carbonyl)-4-piperidinecarboxamide

[0639]

[0640] To a solution of 4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-[(1,1diemthylethoxy)-carbonyl]piperidinecarboxylic acid (6.25 g, 11.5 mmol) prepared using techniques discussed elsewhere herein was added 50% trifluoroacetic acid solution in dichloromethane (100 mL) and stirred 1 hour at room temperature. The solvent was evaporated to afford 9.91 g of an oil. The oil was dissolved in acetonitrile (50 mL) and water (50 mL). To the solution was added sodium carbonate to a pH-9-10 followed by a solution of N-(9-fluorenylmethoxy-carbonyloxy)succinimide (3.88 g, 11.5 mmol) in acetone (25 mL). The pH value of the solution was adjusted to 9-10 with sodium carbonate. The reaction mixture was stirred 16 hours. To the reaction mixture was added 2M aqueous hydrochloric acid to a pH value of about 3. The solution was extracted with dichloromethane (3×100 mL). The combined organics were dried over magnesium sulfate, filtered and the solvent evaporated to afford N-hydroxy-4 [[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide (8.15 g) as a yellow oil. MS (ES) m/z 668 (M+H)⁺.

EXAMPLE 90 Preparation of N-hydroxy-4 [[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide

[0641]

[0642] Using the method of Example 89, N-hydroxy-4-[[4-(4-trifluoromethyl-phenoxy)phenyl] sulfonyl]-1-(9-fluorenyl-methoxycarbonyl)-4-piperidinecarboxamide was prepared from 4-[[4-(4-trifluoromethylphenoxy)-phenyl]-sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]-piperidinecarboxylic acid, which itself was prepared using techniques discussed elsewhere herein. MS (ES) m/z 652 (M+H)⁺.

EXAMPLE 91 Preparation of N-hydroxy-4-[[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide

[0643]

[0644] Step 1: Preparation of Resin MT-I. To a solution of N-hydroxy-4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxy-carbonyl)-4-piperidinecarboxamide of Example 89 (11.5 mmol) in dimethylformamide (75 mL) were added resin I (Floyd et al., Tetrahedron Lett. 1996, 37, 8045-8048) (7.0 g, 7.67 mmol), pyBOP (8.0 g) and N-methylmorpholine (5.05 mL), and the mixture was stirred with an overhead stirrer 4 days. The resin was filtered and washed with dimethylformamide (3×50 mL), methanol (3×50 mL), dichloromethane (3×50 mL) and ether (3×50 mL). The resin was dried in vacuo to provide resin MT-I.

[0645] Step 2: Fmoc deprotection of Resin MT-I. Resin MT-I was swelled with dimethylformamide (2×100 mL) and drained. To swollen resin MT-1, was added a 20% solution of piperidine in dimethylformamide (100 mL). After 1 hour, the resin was drained and retreated with 20% piperidine in dimethylformamide (100 mL). After 15 minutes the resin was filtered and washed with dimethylformamide (3×100 mL), methanol (3×100 mL), dichloromethane (3×100 mL) and ether (3×100 mL). The resin was dried in vacuo to afford resin MT-II (7.23 g).

[0646] Step 3: Preparation of N-hydroxy-4-[[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide from Resin MT-II. To a suspension of resin MT-II (250 mg) in dichloromethane (2 mL) was added diisopropyl-ethylamine (165 μL) and benzoyl chloride (110 μL) and agitated 3 hours. The resin was filtered and washed with dichloromethane (2×10 mL) and methanol (2×10 mL). To the resin was added a solution of 95% trifluoroacetic acid in water and agitated for 1 hour. The resin was drained and washed with methanol (1×2 mL) and dichloromethane (1×2 mL). The filtrate was evaporated. The residue was purified by RPHPLC to afford N-hydroxy-4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide (9.8 mg) as a solid. MS (ES) m/z 565 (M+H)⁺.

EXAMPLE 92 Preparation of N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide

[0647]

[0648] N-hydroxy-4-[[4-(4-trifluoromethyl-phenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide was prepared by the method of Example 91 from N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide (the product of Example 90). MS (ES) m/z 549 (M+H)⁺.

EXAMPLE 93 Preparation of N-(2-tetrahydropyranoxy) -4-[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-4-piperidinecarboxamide

[0649]

[0650] Step 1: Boc deprotection of ethyl 4-[[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]piperidinecarboxylate. To a solution of ethyl 4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)-carbonyl]piperidinecarboxylate (12.58 g, 19.1 mmol; see Example 89) in dichloromethane (50 mL) was added trifluoroacetic acid (50 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to afford a pale yellow oil.

[0651] Step 2: Cbz protection of step 1. The material from step 1 was dissolved in dichloromethane (200 mL). To this solution was added diisopropyl-ethylamine (33.3 mL) and benzyl chloroformate (5.5 mL) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2M aqueous hydrochloric acid to a pH value of about 1 and extracted with dichloromethane (2×100 mL). The combined organics were washed with 2M aqueous HCl (1×100 mL) and brine (1×100 mL), dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow oil.

[0652] Step 3: Hydrolysis of the product of step 2. The material prepared in step 2 was dissolved in tetrahydrofuran (100 mL) and ethanol (50 mL). To this solution was added 1M aqueous sodium hydroxide (50 mL) and 50% aqueous sodium hydroxide (10 mL) and stirred 16 hours. To the solution was added 50% aqueous sodium hydroxide (2 mL) and stirred and additional 24 hours. The tetrahydrofuran and ethanol were evaporated. The pH value of the solution was adjusted to pH about 1 with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×100 mL), washed with brine (1×100 mL), dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow oil.

[0653] Step 4: Cbz deprotection of step 3. The material prepared in step 3 was dissolved in ethanol (100 mL). This solution was added to 10% palladium on carbon (1.0 g). The solution was placed under 45 psi hydrogen. Additional catalyst was added at 6 hours (1.75 g) and 20 hours (1.0 g 4% Pd/C). After 48 hours the reaction mixture was filtered through a plug of Celite. The filtrate was evaporated and triturated with ether to afford N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide (4.47 g) as a white solid. MS (ES) m/z 545 (M+H)⁺.

EXAMPLE 94 Preparation of N-(2-tetrahydro-pyranoxy)-4[[4-(4-trifluoromethyl-phenoxy)phenyl]sulfonyl]-4-piperidine-carboxamide

[0654]

[0655] N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide was prepared by the method of Example 93 starting from ethyl 4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]piperidinecarboxylate (see Example 90). MS (ES) m/z 529 (M+H)⁺.

EXAMPLE 95 Preparation of N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(2-fluorophenyl-carbonyl)-4-piperidinecarboxamide

[0656]

[0657] To a solution of N-(2-tetrahydropyranoxy)-4 [[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94, (50 mg) dissolved in dichloromethane (2.5 mL) was added PS-NMM (135 mg, Argonaut) and 2-fluorobenzoyl chloride (12.1 μL) and stirred for 2 hours. To the reaction mixture was added PS-trisamine (50 mg, Argonaut) and the mixture was stirred 1 hour. The reaction mixture was filtered and washed with dichloromethane (2×2 mL) and methanol (1×2 mL). The combined organics were evaporated to afford N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(2-fluorophenylcarbonyl)-4-piperidinecarboxamide (53.5 mg) as a white solid. MS (ES) m/z 583 (M+H)⁺.

EXAMPLES 96-124

[0658] The following hydroxamic acids were prepared by the method of Example 95 using the appropriate acylating agent.

MS (ES) Example R Acylating Agent m/z 96 3-fluorophenyl 3-fluorobenzoyl 583 (M + H)⁺ chloride 97 4-fluorophenyl 4-fluorobenzoyl 583 (M + H)⁺ chloride 98 2-trifluoro- 2-trifluoromethyl- 633 (M + H)⁺ methylphenyl benzoyl chloride 99 3-trifluoro- 3-trifluoro- 633 (M + H)⁺ methylphenyl methylbenzoyl chloride 100 phenylmethyl phenylacetyl chloride 579 (M + H)⁺ 101 2-tolyl 2-toluoyl chloride 579 (M + H)⁺ 102 4-tolyl 4-toluoyl chloride 579 (M + H)⁺ 103 4-methoxy- methyl 4- 623 (M + H)⁺ carbonylphenyl chlorocarbonyl benzoate 104 4-methoxyphenyl 4-anisoyl chloride 595 (M + H)⁺ 105 2-thienyl 2-thiophenecarbonyl 571 (M + H)⁺ chloride 106 2-furyl 2-furoyl chloride 555 (M + H)⁺ 107 3-pyridyl nicotinoyl chloride 566 (M + H)⁺ 108 4-pyridyl isonicotinoyl 566 (M + H)⁺ chloride 109 c-propyl cyclopropanecarbonyl 529 (M + H)⁺ chloride 110 trichloromethyl trichloroacetic 622 (M + H)⁺ anhydride 111 trifluoromethyl trifluoroacetic 574 (M + H)⁺ anhydride 112 pentafluorophenyl pentafluorobenzoyl 655 (M + H)⁺ chloride 113 4-nitrophenyl 4-nitrobenzoyl 610 (M + H)⁺ chloride 114 4-trifluoro- 4-trifluoromethyl- 633 (M + H)⁺ methylphenyl benzoyl chloride 115 4-trifluoro- 4-trifluoromethoxy- 649 (M + H)⁺ methoxyphenyl benzoyl chloride 116 4-methoxy- 4-methoxyphenyl- 609 (M + H)⁺ phenylmethyl acetyl chloride 117 3-methoxyphenyl 3-anisoyl chloride 595 (M + H)⁺ 118 2-methoxyphenyl 2-anisoyl chloride 595 (M + H)⁺ 119 3,5- 3,5-dimethoxybenzoyl 625 (M + H)⁺ dimethoxyphenyl chloride 120 3,4- 3,4-dimethoxybenzoyl 625 (M + H)⁺ dimethoxyphenyl chloride 121 2,5- 2,5-difluorobenzoyl 601 (M + H)⁺ difluorophenyl chloride 122 methoxy- methyl malonyl 561 (M + H)⁺ carbonylmethyl chloride 123 4-dimethyl- 4-dimethylamino- 608 (M + H)⁺ aminophenyl benzoyl chloride 124 1,1-dimethylethyl pivaloyl chloride 545 (M + H)⁺

EXAMPLES 125-138

[0659] The following hydroxamic acids were prepared by the method of Example of 95 using the appropriate isocyanate as the acylating agent.

Ex- MS (ES) ample RNCO Isocyanate m/z 125

Phenyl isocyanate 580 (M + H) 126

4-Fluorophenyl isocyanate 598 (M + H) 127

4-Methoxybenzyl isocyanate 624 (M + H) 128

Ethyl isocyanate 532 (M + H) 129

3-Trifluoromethyl phenyl isocyanate 648 (M + H) 130

3-Isocyanate propionic acid 576 (M + H) 131

3-Pyridyl isocyanate 581 (M + H) 132

4-Chlorophenyl isocyanate 614 (M + H) 133

3-Fluorophenyl isocyanate 598 (M + H) 134

4-Acetylphenyl isocyanate 622 (M + H) 135

2-Fluorophenyl isocyanate 598 (M + H) 136

4-(Methylthio) phenyl isocyanate 626 (M + H) 137

Benzyl isocyanate 594 (M + H) 138

3-Cyanophenyl isocyanate 605 (M + H)

EXAMPLES 140-143

[0660] The following hydroxamic acids were prepared by the method of Example 95 using the appropriate acylating agent (electophile) and starting from N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94.

Ex- am- MS ple R Electrophile (ES) m/z 140

4-trifluoro- methoxybenzoyl chloride 633 (M + H)⁺ 141

4-trifluoromethyl- phenyl isocyantate 632 (M + H)⁺ 142

4-trifluoro- methylphenyl thioisocyanate 648 (M + H)⁺ 143

4-trifluoromethyl- benzenesulfonyl chloride 653 (M + H)⁺

EXAMPLE 144 Preparation of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(4-aminophenylcarbonyl)-4-piperidinecarboxamide

[0661]

[0662] A solution of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(4-nitrophenylcarbonyl)-4-piperidinecarboxamide, the product of Example 113, (56.0 mg) dissolved in acetic acid (2.5 mL) was added to 4% palladium on carbon (20 mg) and placed under 43 psi hydrogen gas for 2.5 h. The reaction mixture was filtered through a pad of celite. The solvent was evaporated to afford N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(4-aminophenylcarbonyl)-4-piperidinecarboxamide (50.2 mg) as a pale yellow solid. MS (ES) m/z 580 (M+H)⁺.

EXAMPLE 145 Preparation of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(4-carboxyphenylcarbonyl)-4-piperidinecarboxamide

[0663]

[0664] To a solution of the product of Example 103 (57 mg) dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL) was added 1M aqueous sodium hydroxide solution (1 mL) plus 50% aqueous sodium hydroxide (50 μL) and the reaction mixture was stirred 2 hours. The pH value of the reaction mixture was adjusted to 1 with 6M hydrochloric acid. The solution was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by RPHPLC to afford the acid N-hydroxy-4[[4-(4-trifluoromethyl-phenoxy)phenyl]sulfonyl]-1-(4-carboxyphenylcarbonyl)-4-piperidinecarboxamide (12.8 mg). MS (ES) m/z 631 (M+NH₄)⁺.

EXAMPLE 146 Preparation of N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide

[0665]

[0666] Step 1: Hydrolysis of methyl 4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxylate. To a solution of methyl 4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxylate (10.0 g, 31 mmol) dissolved in tetrahydrofuran (150 mL) was added potassium trimethylsilanolate (12.1 g) and stirred 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate (2×100 mL). The pH value of the aqueous layer was adjusted to 2 with 2M hydrochloric acid and extracted with ethyl acetate (2×100 mL). The latter organics were washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow solid (8.20 g).

[0667] Step 2: Loading on resin. The compound obtained in step 1 (4.0 g, 13.1 mmol) was dissolved in 1-methyl-2-pyrrolidinone (15 mL) and added to a suspension of resin I (6.0 g, 6.6 mmol; Preparative Example XI) in 1-methyl-2-pyrrolidinone (40 mL). To this solution were added pyBOP (6.85 g) and N-methylmorpholine (2.9 mL), and the mixture was stirred with overhead stirring 16 hours. The resin was filtered and washed with dimethylformamide (3×50 mL), methanol (3×50 mL), dichloromethane (3×50 mL) and ether (3×50 mL). The resin was dried in vacuo to provide resin MT-III (6.79 g).

[0668] Step 3: Aryl fluoride displacement of resin MT-III. A suspension of resin MT-III (200 mg, 0.17 mmol), 1-methyl-2-pyrrolidinone (2 mL), cesium carbonate (560 mg) and 4-methoxyphenyl (306 mg) were stirred at 105° C. for 16 hours. The reaction mixture was cooled and the resin filtered. The resin was washed with dimethylformamide (3×5 mL), methanol (3×5 mL), 10% aqueous acetic acid (3×5 mL), methanol (3×5 mL) and dichloromethane (3×5 mL). To the resin was added 95% aqueous trifluoroacetic acid and the reaction mixture was agitated for 1 hour. The resin was drained and washed with dichloromethane (2×1 mL). The solvent was evaporated. The residue was purified by RPHPLC to provide N-hydroxy-4-[[4-(4-methoxy-phenoxy)phenyl]sulfonyl]-4-thianecarboxamide (17.9 mg) as a pale yellow oil.

EXAMPLES 147-151

[0669] The following hydroxamic acids were prepared by the method of Example 146 using the appropriate alcohol.

Example R Alcohol MS (ES) m/z 147 4-trifluoro- 4-trifluoro- 495 (M + NH₄)⁺ methoxyphenyl methoxyphenol 148 4-isopropyl- 4-isopropylphenol 453 (M + NH₄)⁺ phenyl 149 3-pyridyl 3-hydroxypyridine 395 (M + H)⁺ 150 3,4-dimethoxy- 3,4-dimethoxyphenol 471 (M + NH₄)⁺ phenyl 151 4-pyridyl 4-hydroxypyridine 395 (M + H)⁺

EXAMPLES 152-155

[0670] The following hydroxamic acids were prepared by the method of Example 146 using the appropriate amine.

Example R Amine MS (ES) m/z 152 4-(4-fluoro- 4-(4-fluorobenzoyl)- 507 (M + H)⁺ benzoyl)piperidyl piperidine 153 4-(2-methoxy- 4-(2-methoxyphenyl)- 491 (M + H)⁺ phenyl)piperidyl piperidine 154

N-cyclopropyl-meth- yl-N-methyl-4-pipe- ridine carboxamide 496 (M + H)⁺ 155 pyrrolidinyl pyrrolidine 371 (M + H)⁺

Example 156 Preparation of N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide-1,1-dioxide

[0671]

[0672] Step 1: Oxidation of Resin MT-III. A suspension of resin MT-III (2.0 g, 1.72 mmol), m-perbenzoic chloroperbenzoic acid (4.37 g) and dichloromethane 25 mL) was stirred at room temperature for 20 hours. The resin was filtered and washed with dichloromethane (3×25 mL), dimethylformamide (3×25 mL), methanol (3×25 mL), 1M aqueous sodium bicarbonate (2×25 mL), methanol (3×25 mL), dichloromethane (3×25 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-IV (2.16 g).

[0673] Step 2: Aryl fluoride displacement of resin MT-IV. N-hydroxy-4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxamide 1,1-dioxide was prepared by the method of Example 146 using resin MT-IV in the place of resin MT-III. ES (MS) m/z 473 (M+NH₄)⁺.

EXAMPLES 156-160

[0674] The following hydroxamic acids were prepared by the method of Example 156 using the appropriate alcohol.

Example R Alcohol MS (ES) m/z 157 4-trifluoro- 4-trifluoro- 527 (M + NH₄)⁺ methoxyphenyl methoxyphenol 158 4-isopropylphenyl 4-isopropylphenol 485 (M + NH₄)⁺ 159 3-pyridyl 3-hydroxypyridine 427 (M + H)⁺ 160 4-pyridyl 4-hydroxypyridine 427 (M + H)⁺

EXAMPLE 161

[0675] The following hydroxamic acids were prepared by the method of Example 156 using the appropriate amine.

Example R Amine MS (ES) m/z 161 4-(4-fluorobenzoyl) 4-(4-fluoro- 539 (M + H)⁺ piperidyl benzoyl)- piperidine

Example 162 Preparation of N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]-piperidyl]phenyl]sulfonyl]-4-thianecarboxamide

[0676]

[0677] Step 1: Aryl fluoride displacement of Resin MT-III. To a suspension of resin MT-III (4.06 g, 3.4 mmol) in 1-methyl-2-pyrrolidinone (40 mL) was added ethyl isonipecotate (5.25 mL), and the mixture was heated to 100° C. for 16 hours. The cooled reaction mixture was filtered and the resin was washed with methanol (3×25 mL), dichloromethane (1×10 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-V (4.21 g).

[0678] Step 2: Hydrolysis of resin MT-V. To a suspension of resin MT-V (4.13 g) in tetrahydrofuran (20 mL) was added 4M aqueous potassium hydroxide (10 mL) and stirred at room temperature for 5 days. The resin was filtered and washed with methanol (3×25 mL), dichloromethane (3×25 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-VI.

[0679] Step 3: Conversion to amide. To a suspension of resin MT-VI (268 mg) in 1-methyl-2-pyrrolidinone (2 mL) were added 3,5-dimethyl-piperidine (299 μL), pyBOP (587 mg) and diisopropylethyl amine (393 μL), and mixture was stirred 40 hours. The resin was filtered and washed with dimethylformamide (3×2 mL), methanol (3×2 mL), 10% aqueous acetic acid (3×2 mL), methanol (3×2 mL), dichloromethane (3×2 mL) and glacial acetic acid (1×2 mL). The resin was treated with 95% aqueous trifluoroacetic acid (2 mL) and agitated 1 hour. The resin was washed with dichloromethane (2 mL) and methanol (2 mL). The filtrate was evaporated. The residue was purified by RPHPLC to afford N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]piperidyl] phenyl]sulfonyl]-4-thianecarboxamide (7.5 mg) MS (ES) m/z 524 (M+H)⁺.

EXAMPLE 163 Preparation of N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]-piperidyl]phenyl]sulfonyl]-4-thianecarboxamide

[0680] N-hydroxy-4-[[4-[4-[(3,5-dimethyl-piperidyl)carbonyl]piperidyl]phenyl]sulfonyl]-4-thianecarboxamide was prepared by the method of using cis-2,6-dimethylmorpholine as the amine. MS (ES) m/z 526 (M+H)⁺.

EXAMPLE 164 N-hydroxy-4[[[4-[4-(4-fluorophenyl)-methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide

[0681]

[0682] Step 1: Preparation of amine 4-(4-fluorophenyl)methoxy piperidine. Ninety-five percent dry sodium hydride is weighted in a 25 mL vial. Boc-(4-hydroxy)-piperidine (1 g, 4.97 mmol) in 10 mL of dimethyl formamide is added and the reaction mixture is stirred at room temperature for 15 minutes 4-fluoro benzyl bromide (1.4 g, 7.5 mmol) is added and the reaction mixture is stirred at room temperature for 16 hours, then quenched with water and diluted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10. The Boc-protected amine is dissolved in 3 mL of dichloromethane and 3 mL of trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 hours and the solvent is evaporated to give 1.8 g of 4-(4-fluorophenyl)-methoxy piperidine. MS: M+H=210.1319.

[0683] Step 2: Preparation of N-hydroxy-4 [[[4-[4-(4-fluorophenyl)methoxy] piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. To a solution of N-tetrahydropyranoxy-4-fluorophenyl-sulfonyl-1-tetrahydropyrancarboxamide (100 mg, 0.26 mmol) in 1.5 mL of DMA are added the amine from step 1 (0.52 mmol, 2 eq.) and cesium carbonate (420 mg, 1.29 mmol). The reaction mixture is stirred at 100° C. for 48 hours. The reaction is treated with water and filtered through Celite eluting with dichloromethane. The solvent was evaporated and the residue is dissolved in 2 mL of 4M HCl in dioxane. The mixture is stirred at room temperature for 1 hour and 1 mL of methanol is added. After stirring 15 minutes at room temperature, the solvent is evaporated and the residue was purified by RPHPLC eluting with 10% to 90% acetonitrile/water to give N-hydroxy-4-[[[4-[4-(4-fluorophenyl)methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+H=493.1792.

EXAMPLES 165-181

[0684] The following hydroxamic acids were synthesized by the procedure of Example 164:

HI Ex- Halide starting RES MS ample material R M + H 165 benzyl bromide

475.1913 166 ethyl iodide

413.1764 167 4-fluoro benzyl bromide

493.1792 168 iodopropane

427.1918 169 3,5-dimethyl benzyl bromide

144.1391 170 4-chloro benzyl bromide

509.1515 171 3-methyl benzyl bromide

489.2059 172 4-methyl benzyl bromide

489.2074 173 3-trifluoro- methoxy benzyl bromide

559.1738 174 2-trifluoro- methyl benzyl bromide

543.1780 175 4-trifluoro- methoxy benzyl bromide

559.1730 176 3,4-dichloro- benzyl bromide

543.1155 177 3-trifluoro- methyl benzyl bromide

543.1779 178 3,5-dimethoxy- benzyl bromide

535.2120 179 3,4-difluoro- benzyl bromide

511.1705 180 4-cyano- benzyl bromide

500.1835 181 2-phenyl benzyl bromide

551.2196

Example 182 N-hydroxy-4-[[[4-[3-(4-fluorophenyl)-methoxy]piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide

[0685]

[0686] N-hydroxy-4[[[4-[3-(4-fluorophenyl)-methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydro-pyrancarboxamide is prepared by the method of Example 164 starting from Boc-(3-hydroxy)-piperidine in step 1.

Examples 183-184

[0687] The following hydroxamic acids were synthesized using a procedure similar to that of Example 182:

Halide starting Example material R HI RES MS 183 4-fluroro benzyl bromide

M + H =475.1913 184 benzyl bromide

M + H =551.2196

Example 185 N-hydroxy-4[[[4-(4-phenoxy)-piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide

[0688]

[0689] N-hydroxy-4 [[[4-(4-phenoxy)piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide is prepared by the method of Example 164 starting from 4-phenoxypiperidine in step 2.

Examples 186-187

[0690] The following hydroxamic acids were synthesized using a procedure similar to that of Example 185:

Ex- ample Amine starting material R HI RES MS 186 187

H 3,5-di- methyl M + H = 461.1749 M + H = 489.2065

Example 188 Preparation of N-hydroxy-4[[[4-[(3-trifluoromethyl)phenylcarbamoxy]-piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide

[0691]

[0692] Step 1: A solution of N-tetrahydro-pyranoxy-4-fluorophenylsulfonyl-1-tetrahydro-pyrancarboxamide (1 g, 2.58 mmol), 4-hydroxy-piperidine (392 mg, 3.87 mmol) and cesium carbonate (2.52 g, 7.74 mmol) in 20 mL of NMP is stirred at 100° C. for 48 hours. The reaction mixture is treated with water and neutralized to pH 4 with 5% aqueous HCl. The aqueous layer is extracted twice with ethyl acetate and the combined organic layer is dried using magnesium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give N-tetrahydropyranoxy-4-[[(4-hydroxypiperidyl) phenyl] sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+Na=491.2.

[0693] Step 2: To a solution of alcohol N-tetrahydro-pyranoxy-4[[(4-hydroxypiperidyl)-phenyl]sulfonyl]-1-tetrahydropyrancarboxamide (50 mg, 0.107 mmol) in 2 mL of dichloromethane is added alpha, alpha, alpha-trifluoro-M-tolyl isocyanate (21 mg, 0.112 mmol). The reaction mixture is stirred for 16 hours at room temperature and 21 mg of alpha,alpha,alpha-trifluoro-m-tolyl isocyanate is added. The mixture is stirred 48 hours at room temperature and treated with water. The solvent is evaporated and the residue is dissolved in 2 mL of 4M HCl in dioxane. The mixture is stirred at room temperature for 1 hour and 1 mL of methanol is added. After stirring 15 minutes at room temperature the solvent is evaporated and the residue was purified by RPHPLC eluting with 10% to 90% acetonitrile/water to give N-hydroxy-4-[[[4-[(3-trifluoromethyl)phenyl-carbamoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+Na=594.1.

EXAMPLES 189-191

[0694] The following hydroxamic acids were synthesized using a procedure similar to that of Example 188:

Example Isocyanate starting material R MS 189 alpha,alpha,alpha-tri- fluoro-M-tolyl isocyanate

M + Na = 594.1 190 4-ethoxyphenyl isocyanate

M + Na = 570.2 191 4-fluorophenyl isocyanate

M + H = 522.1742

Example 192 Preparation of N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]-sulfonyl]-1-[[(2-trifluoromethoxy)-phenyl]-sulfonyl-4-piperidinecarboxamide

[0695]

[0696] N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-1-[[(2-trifluoromethoxy)phenyl]-sulfonyl-4-piperidinecarboxamide can be prepared using the method of Example 93 starting from 2-trifluoromethoxybenzene sulfonyl chloride.

EXAMPLES 193-197

[0697] The following hydroxamic acids were synthesized using a procedure similar to that of Example 192:

Sulfonyl chloride Example starting material R MS 193 2-trifluoro- methoxybenzene sulfonyl chloride

M + NH4 =702.1003 194 benzene sulfonyl chloride

M + NH4 =618.1216 195 alpha- toluenesulfonyl chloride

M + NH4 =632.1337 196 3-trifluoro- methylbenzene sulfonyl chloride

M + NH4 =686.1027 197 3-trifluoro- methane sulfonyl chloride

M − H =591.1

EXAMPLE: 198

[0698]

[0699] N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-1-(N-methylthiourea)-4-piperidinecarboxamide was prepared by the method of Example 192 starting with methyl isothiocyanate. M+H=77.

EXAMPLES 199-202

[0700] The following hydroxamic acids were synthesized using the procedure of Example 198:

Sulfonyl chloride MS Example starting material R M + H 199 2-morpholinoethyl isothiocyanate

633.1643 200 2-piperidinoethyl isothiocyanate

653.1694 201 pyridine-3- isothiocyanate

597.1094 202 4-dimethylaminophenyl isothiocyanate

639.1526

EXAMPLE 203 Preparation of 1,1-dimethylethyl-3,6-dihydro-4-[2-(trifluoromethyl)phenyl]-[(2H)-pyridinecarboxylate

[0701]

[0702] Part A: An oven-dried 1.0 liter flask fitted with a thermometer and nitrogen inlet was charged with 55 mL of a 2 M solution of lithium diisopropoylamide in tetrahydrofuran and 50 mL of tetrahydrofuran. The flask was immersed in a dry ice/acetone bath. When the temperature of the solution was less than −70 degrees, a solution of N-t-butoxycarbonylpiperidinone (20.0 g, 0.1 mole) in 100 mL tetrahydrofuran was added dropwise, maintaining the temperature less than −65 degrees. After complete addition, the flask was stirred with cooling for 20 minutes. Then a solution of N-trifluoromethanesulfonimide (38.2 g, 0.107 mole) was added drop-wise maintaining the temperature less than −65 degrees. After complete addition, the dry ice/acetone bath was swapped with an ice/water bath. The reaction was stirred overnight (about eighteen hours), slowly warming to room temperature. After 16 hours, the solvent was removed in vacuo, and the residue was purified by column chromatography on neutral alumina, yielding 26.53 g of product as a yellow oil. Electrospray mass spectroscopy showed m/z 332 (M+H).

[0703] Part B: A three-necked 15 mL round-bottom flask was charged with the product from Part A (6 g, 18.1 mmol), o-trifluorobenzeneboronic acid (4.94 g, 26 mmol), lithium chloride (2.34 g, 55 mmol), 2 M sodium carbonate (26 mL, 52 mmol) and ethylene glycol dimethyl ether (60 mL). Nitrogen was bubbled through the solution for 10 minutes, then palladium tetrakistriphenylphosphine (1.06 g, 0.92 mmol) was added. The mixture was heated to reflux for 1.5 hours, then cooled to room temperature. The solvent was removed in vacuo, then the residue was partitioned between 100 mL of methylene chloride and 100 mL of 2 M sodium carbonate with 3 mL concentrated ammonium hydroxide. The aqueous layer was extracted with an additional 100 mL methylene chloride, then the combined organic layers were dried over magnesium sulfate and concentrated to give 8.42 g of crude product as a dark brown oil. Purification via flash column chromatography (10% ethyl acetate3/hexanes) yielded 2.76 g of pure product as a yellow oil. Electrospray mass spectroscopy showed m/z 328 (M+H).

EXAMPLE 204 Preparation of 1,2,3,6-tetrahydro-4-[2-trifluoromethyl)phenyl]pyridine

[0704]

[0705] The title compound of Example 203 (300 mg, 0.92 mmol) was dissolved in methylene chloride (5 mL) in a 15 mL round-bottom flask, and 5 mL of trifluoroacetic acid was added dropwise. After 15 minutes, the solvent was removed in vacuo, and the residue partitioned between 20 mL of ethyl acetate and 20 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 195 mg of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 228 (M+H).

EXAMPLE 205 Preparation of 4-[2-(trifluoromethyl) phenyl]piperidine

[0706]

[0707] Part A: A solution of the title compound of Example 203 (2.3 g, 7 mmol) in 20 mL ethanol was added to a hydrogenation flask containing 1 g of 4% palladium on carbon (0.38 mmol). The mixture was placed under 100 PSI hydrogen and heated to 50 degrees Celsius for 5 hours. Then the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo to give 2.27 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 330 (M+H).

[0708] Part B: The product from Part A above (2.24 g, 6.8 mmol) was dissolved in 100 mL methylene chloride, and 100 mL of trifluoroacetic acid was added dropwise. After 15 minutes, the solvent was removed in vacuo, and the residue partitioned between 100 mL of ethyl acetate and 100 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 1.12 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 230 (M+H).

EXAMPLE 206 General Description for Preparation of Hydroxamic Acids via Aryl Fluoride Displacement with Amines.

[0709] Part A: A 2 dram vial was charged with aryl fluoro compound of Preparative Example IV (170 mg, 0.44 mmol), 1 ml of 2-methylpyrrolidinone, cesium carbonate (360 mg, 1.1 mmol) and 0.66 mmol of an amine. A small magnetic stirring bar was added, then the vial was capped and placed in a Pierce Reacti-therm™ at 115 degrees Celsius. The reaction progress was followed by analytical HPLC. When the reaction was greater than 90% complete, the vial was cooled to room temperature. The reaction mixture was diluted with 5 mL of water, then 1.2 mL of 5% hydrogen chloride/water was added dropwise. Then, the entire mixture was poured onto a column of Celite. The column was washed exhaustively with ethyl acetate (30-40 mL) and the filtrate was collected and concentrated to give the crude products.

[0710] Part B: The product from above was dissolved in 2 mL 1,4-dioxane and 2 mL of methanol in a 4 dram vial with a small magnetic stirring bar. A solution of 4 N hydrogen chloride in 1,4-dioxane was carefully added to the reaction, and the mixture was stirred for 2 hours. Then the solvent was removed in vacuo and the residue purified by preparative reversed-phase HPLC.

EXAMPLES 207-214

[0711] The following hydroxamic acids were prepared using the method described above in Example 106 with the indicated amine as the starting material.

m/z from electrospray mass Example amine R spectroscopy 207 Product of Example 205

513.3 (M + H) 208 Product of Example 204

511.2 (M + H) 209 piperidine

369.2 (M + H) 210 tetrahydro- piperidine

367.2 (M + H) 211 4-(2-keto- benzimid- azolinyl)- piperidine

501 (M + H) 212 hexamethyl- eneimine

383.2 (M + H) 213 1-methylhomo- piperazine

398.2 (M + H) 214 1,3,3-trimethyl- 6-azabicyclo- [3.2.1]octane

437.3 (M + H)

EXAMPLES 215-223

[0712] Using the procedures outlined in Examples 203, 204, 206 and other methods outlined above, the following analogs are made from the indicated boronic acid:

Example Boronic acid R 215

216

217

218

219

220

221

222

223

EXAMPLE 224 Preparation of Tetrahydro-N-hydroxy-4-[[4-(pentaflourooxy)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide

[0713]

[0714] Part A: To a solution of the product of Preparative Example IV (2.5 g, 6 mmol) in dimethylformamide (50 mL) was added 4-pentafluroethyloxy phenol (2.0 g, 6 mmol) followed by cesium carbonate (5 g, 12 mmol). The reaction was heated at eighty degrees Celsius for twelve hours. Stripping the dimethylformamide in vacuo afforded a brown solid (5.5 g). The product was dissolvent in ethylacetate (150 ml) and extracted with water, brine and dried over sodium sulfate. The ¹H NMR, MS, and HPLC was consistent with desired compound.

[0715] Part B: To the product of part A, crude THP-protected hydroxamate was disolved in acetonitrile/water (40 ml) was slowly added 10% aq HCl (10 ml). After stirring two hours, the acetonitrile was stripped. The resultant precipitate was collected, giving the title compound as a white solid (2.1 g). The ¹H NMR, MS, and HPLC was consistent with desired compound. This solid was recrystallized from ethylacetate and hexanes (1.8 g). The ¹H NMR, MS, and HPLC was consistent with desired compound. MS (CI) M+H calculated for C₂₃H₂₇BrNO₆S: 511, found 511.

EXAMPLE 225 Preparation of Tetrahydro-4-[[4-(pentaflourooxy)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide

[0716]

[0717] Part A. The product of Preparative Example V (2.5 g) was dissolved in methanol (60 mL). To this solution ammonium formate (3 g) was added, followed by Pd on charcoal 20% catalyst. The mixture was heated to reflux for 24 hour. After complete reaction the mixture was cooled filtered through a plug of Celite and the solvent removed under reduced pressure to give pure amide (1.7 g). The ¹H NMR, MS, and HPLC was consistent with desired compound. MS (CI) M+H calculated for C₂₃H₂₇BrNO₆S: 445, found 445.

EXAMPLE 226 Preparation of 4-(4-pyridyloxy) thiophenol hydrochloride

[0718]

[0719] Part A: Phenol (1500 g, 15.9 mol) and 4-chloropyridine hydrochloride (800 g, 7.1 mol) were combined in a melt at 150° C. under a nitrogen atmosphere. After fifteen hours, the reaction was dissolve in 3N sodium hydroxide solution (5400 mL) and extracted with methylene chloride (4×). The organic extracts were combined, washed with 1N sodium hydroxide solution, water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The isolated oil was dissolved in hexanes (1000 mL) and cooled to −60° C. The precipitate was collected and dried in vacuo to yield 452 g (38%) of the 4-phenoxypyridine as a white solid.

[0720] Part B: A solution of the 4-phenylpyridine from part A (400 g, 2.3 mol) in 1,2-dichloroethane (1250 mL) was cooled in an ice bath under a nitrogen atmosphere and treated with chlorosulfonic acid (400 mL, 6.0 mol). The reaction temperature was held below 12° C. during the addition. The reaction was then heated to 45° C. for 15 hours. The standard work-up procedure afforded 270 grams (40%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonic acid.

[0721] Part C: A slurry of the sulfonic acid part B (420 g, 1.5 mol) in acetonitrile (2500 mL) and DMF (40 mL) was warmed to 75° C. under a nitrogen atmosphere and treated with thionyl chloride (243 mL, 3.3 mol) added dropwise over 3 hours. After stirring for one-half hour, the standard work-up procedure afforded 483 grams (100%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonyl chloride hydrochloride.

[0722] Part D: A solution of triphenylphosphine (65.6 g, 250.28 mmol) in dry methylene chloride (240 mL) was cooled to zero degrees C. in an ice-water bath, then treated with dimethylformamide (3.4 mL, 3.2 g, 43.40 mmol). The reaction mixture was then treated with the sulfonyl chloride from part C (25.5 g, 83.43 mmol), added as a solid over one-half hour. After two hours in the ice bath, the reaction was treated with 1 N aqueous hydrochloric acid solution (150 mL) and stirred vigorously for one hour. The layers were separated and the aqueous layer was extracted with methylene chloride (1×). The aqueous layer was concentrated in vacuo to yield 17.9 grams (90%) of the 4-(4-pyridyloxy)thiophenol hydrochloride as a tan solid, m/z=204 (M+H).

EXAMPLE 227 Preparation of

[0723]

[0724] Part A: A solution of 4-(4-pyridyloxy)-thiophenol (2.0 g, 8.34 mmol) and tert-butylbromoacetate (1.2 mL, 1.6 g, 8.34 mmol) in dry methanol (30 mL) was cooled to zero degrees C. and treated with triethylamine (2.4 mL, 1.8 g, 17.52 mmol). The addition was done at a rate which held the reaction temperature below 10° C. The ice bath was removed and after two hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The organic extracts were combined, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to yield 2.3 grams of the tert-butyl ester of the sulfide acid suitable for the next step.

[0725] Part B: To a solution of the tert-butyl ester of the sulfide acid from part A (2.3 g, 7.25 mmol) in dry anisole (85 mL, 8.1 g, 74.67 mmol) was added trifluoroacetic acid (25.5 mL, 37.7 g, 330.6 mmol). After one-half hour at ambient temperature, the reaction was concentrated in vacuo to 3.7 g of the TFA salt of the sulfide acid suitable for the next step.

[0726] Part C: To a solution of the TFA salt of the acid obtained from part B (2.7 g, 7.19 mmol) in dimethylformamide (10 mL) was added N-hydroxybenzotriazole hydrate (1.5 g, 10.79 mmol), N-methylmorpholine (4.7 mL, 4.4 g, 43.16 mmol), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (2.5 g, 21.58 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8 g, 9.35 mmol). After sixteen hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 2.1 g (81%) of the THP sulfide hydroxamate as a dry, white foam, m/z=361 (M+H).

[0727] Part D: To a solution of the THP sulfide hydroxamate from part C (2.1 g, 5.83 mmol) in methanol/water (13 mL/2 mL) was added tetrabutylammonium Oxone (5.8 g, 61.29 mmol). After 2 days at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (6×). The organic extracts were combined, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 0.9 g (40%) of the THP sulfone hydroxamate as a dry, white foam, m/z=393 (M+H).

[0728] Part E: To a slurry of the THP sulfone hydroxamate from part D (0.9 g, 2.29 mmol) in methanol (0.6 mL) was added 4N HCl dioxane solution (6 mL). After one hour at ambient temperature, the reaction mixture was slowly poured into diethyl ether (200 mL). Filtration afforded 0.6 grams (78%) of the title compound as a white solid, m/z=309 (M+H).

EXAMPLE 228 Preparation of

[0729]

[0730] Part A: A solution of 4-(4-pyridyloxy)-thiophenol (18.0 g, 75.08 mmol) and tert-butylbromoacetate (10.5 mL, 13.9 g, 71.33 mmol) in dry methanol (250 mL) was cooled to 0° C. and treated with triethylamine (22.0 mL, 16.0 g, 157.68 mmol). The addition was done at a rate which held the reaction temperature below 1° C. The ice bath was removed and after one-half hour at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The organic extracts were combined, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to yield 21.7 grams of the tert-butyl ester of the sulfide acid suitable for the next step.

[0731] Part B: To a solution of the tert-butyl ester of the sulfide acid from part A (221.7 g, 68.37 mmol) in dry anisole (76.5 mL, 76.1 g, 704.12 mmol) was added trifluoroacetic acid (240 mL, 355 g, 3,117 mmol). After one hour at ambient temperature, the reaction was concentrated in vacuo to yield 34.7 g of the TFA salt of the sulfide acid suitable for the next step.

[0732] Part C: To a solution of the TFA salt of the sulfide acid from part B (34.7 g, 68.37 mmol) in dry methanol (100 mL) was added thionyl chloride (7.5 mL, 12.2 g, 102.5 mmol). After twelve hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to yield 18.7 grams of the methyl ester of the sulfide acid suitable for the next step.

[0733] Part D: To a solution of the methyl ester of the sulfide acid obtained from part C (18.7 g, 67.92 mmol) in methylene chloride (325 mL) was added tetrabutylammonium Oxone (193 g, 543.4 mmol). After 2 days at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (9×). The organic extracts were combined, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 7.3 g (35%) of the methyl ester of the sulfone acid as a dry, white foam, m/z=308 (M+H).

[0734] Part E: To a solution of the methyl ester of the sulfone acid obtained from part D (2.7 g, 8.79 mmol) in dry dimethylformamide (20 mL) was added 18-crown-6 ether (0.5 g, 1.90 mmol) and potassium carbonate (4.9 g, 35.14 mmol). The reaction slurry was treated with bis-(2-bromoethyl)ether (1.1 mL, 2.0 g, 8.79 mmol) and then heated to 60° C. After fifteen hours at 60° C., the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with brine (3×), dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography (on silica, NH₃-methanol-ethyl acetate/hexanes) afforded 1.6 g (48%) of the THP sulfone methyl ester as a tan solid, m/z=378 (M+H).

[0735] Part F: To a solution of the THP sulfone methyl ester from part E (1.6 g, 4.24 mmol) in dry tetrahydrofuran (20 mL) was added potassium trimethylsilanoate (1.6 g, 12.72 mmol). After five hours at ambient temperature, the reaction was concentrated in vacuo to yield the potassium salt of the THP sulfone acid as a tan solid suitable for use in the next step.

[0736] Part G: To a slurry of the potassium salt of the THP sulfone acid obtained from part F (1.7 g, 4.24 mmol) in dimethylformamide (20 mL) was added N-hydroxybenzotriazole hydrate (1.1 g, 8.48 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g, 8.48 mmol). After heating the reaction mixture at 40° C. for one-half hour, N-methylmorpholine (1.4 mL, 1.3 g, 12.72 mmol) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.0 g, 8.48 mmol) were added. After heating at 45° C. for 15 hours, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% potassium carbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (13×). The organic extracts were combined, washed with water and brine (3×), dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography (on silica, (2M ammonia in methanol-ethyl acetate)/hexanes) afforded 0.7 g (35%) of the THP-protected THP sulfone hydroxamate as a dry, white foam, m/z=463 (M+H).

[0737] Part H: To a slurry of the THP-protected THP sulfone hydroxamate from part G (0.7 g, 1.43 mmol) in methanol (0.4 mL) was added 4N HCl dioxane solution (4 mL). After thirty minutes at ambient temperature, the reaction mixture was slowly poured into diethyl ether (200 mL) and stirred for fifteen minutes. Filtration afforded 0.5 grams (83%) of the title compound as the HCl salt, m/z=379 (M+H).

EXAMPLE 229 Preparation of N-hydroxy-1-(4-methyl-phenyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monohydrochloride

[0738]

[0739] Part A: To a suspension of ethyl 4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate, hydrochloride Preparative Example II (2.56 g, 7.28 mmol) in H₂O (50 mL) was added 1.25N NaOH (pH=9.0). The aqueous layer was extracted with diethyl ether (2×75 mL). The combined organic layers were washed with saturated NaCl and dried over Na₂SO₄. Concentration in vacuo provided the free amine as an off-white solid (1.72 g). To a solution of the free amine (1.70 g, 5.39 mmol) in toluene (25 mL) was added Cs₂CO₃ (2.34 g, 7.19 mmol) and a solution of 4-bromotoluene (0.877 g, 5.13 mmol) in toluene (5 mL). This was followed by the addition of tris(dibenzyldeneacetone)dipallidium (O) (0.047 g, 0.0513 mmol) and BINAP (0.096 g, 0.154 mmol). The resulting mixture was then heated to one hundred degress Celsius for 17 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate and the filtrate was concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexane) provided the aniline as a yellow oil (1.59 g, 76%).

[0740] Part B: To a solution of the aniline of part A (1.56 g, 3.85 mmol) in N,N-dimethylformamide (8.0 mL) was added K₂CO₃ (1.06 g, 7.70 mmol) and 4-(trifluoromethoxy)phenol (0.823 g, 4.62 mmol). The resulting mixture was heated to ninety degrees Celsius for 19 hours. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between H₂O and diethyl ether. The organic layer was washed with saturated NaCl and dried over Na₂SO₄. Concentration in vacuo provided the biaryl ether as a brown oil (2.42 g, >100%).

[0741] Part C: To a solution of the biaryl ether of part B (2.42 g, 3.85 mmol) in tetrahydrofuran (10 mL) and H₂O (10 mL) was added NaOH (1.54 g, 38.50 mmol) in H₂O (5.0 mL). The mixture was heated to sixty degrees Celsius for 6 hours then cooled to ambient temperature. The mixture was then acidified (pH=7) with 1N HCl. The solids were collected by vacuum filtration, then suspended in acetonitrile and concentrated in vacuo to give the acid as a tan solid (1.95 g, 95%).

[0742] Part D: To a suspension of the acid of part C (1.95 g, 3.64 mmol) in N,N-dimethylformamide (15 mL) was added 1-hydroxybenzotriazole (0.596 g, 4.37 mmol), N-methylmorpholine (1.19 mL, 10.92 mmol), 0-(tetrahydropuranyl) hydroxylamine (1.28 g, 10.92 mmol) and 1-3-[(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.977 g, 5.10 mmol). The resulting mixture was stirred at ambient temperature for 16 hours then concentrated in vacuo. The residue was partitioned between H₂O and ethyl acetate. The combined organic layers were washed with H₂O, saturated NaHCO₃, saturated NaCl and dried over Na₂SO₄. Chromatography (on silica, methanol/ethyl acetate) provided the protected hydroxamate as a pale-yellow foam (1.90 g, 83%).

[0743] Part E: To the protected hydroxamate of part D (1.89 g, 3.00 mmol) was added 4N HCl in dioxane (7.50 mL, 30.0 mmol) and methanol (1.22 mL, 30.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hours, then diethyl ether (5 mL) was added and the precipitate was collected by filtration to provide the title compound as a fine white solid (1.56 g, 89%). MS MH⁺ calculated for C₂₆H₂₅O₆N₂S₁F₃: 551, found 551.

EXAMPLE 230 Preparation of N-hydroxy-1-(2-hydroxyethyl)-4-[4-(4-trifluoro-methoxyphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, hydrochloride

[0744]

[0745] Part A: Ethyl 4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate, hydrochloride (3.95 g, 11.3 mmol) Preparative Example II, powdered potassium carbonate (3.45 g, 25 mmol), and N,N-dimethylformamide (11.3 mL) were combined. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (1.85 mL, 12 mmol) was added and the mixture was stirred for 48 hours at ambient temperature. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (100 mL, then 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed to afford the desired tetrahydropyranyl ether as an oil (4.44 g, 88%)

[0746] Part B: The tetrahydropyranyl ether from Part A was stirred at 110 degrees Celsius for 20 hours in the presence of powdered potassium carbonate (2.07 g, 15 mmol), 4-(trifluoromethoxy)phenol (2.67 mL, 15 mmol), and N,N-dimethyformamide (5 mL). The mixture was diluted with saturated sodium bicarbonate (50 mL) and was extracted with ethyl acetate (150, then 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed to afford the desired aryl ether as an oil (5.72 g, quantitative).

[0747] Part C: The aryl ether from Part C (1.28 g, 2.1 mmol) was refluxed in the presence of potassium hydroxide (954 mg, 16.8 mmol), ethanol (9 mL), and water (3 mL). After 2 hours, the reaction vessel was cooled to zero degrees Celsius. Concentrated hydrochloric acid was added drop-wise to adjust the pH to 4.0. The acidified reaction was concentrated, azeotroped with acetonitrile, and dried in vacuo, affording the crude carboxylic acid, which was used directly in Part D.

[0748] Part D: The carboxylic acid from Part C was converted to O-tetrahydropyranyl hydroxamate using O-tetrahydropyranyl hydroxylamine (351 mg, 3 mmol), N-methylmorpholine (0.5 mL), N-hydroxybenzotriazole (405 mg, 3 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (573 mg, 3 mmol) in N,N-dimethylformamide (9 mL). The tetrahydropyranyl hydroxamate (855 mg, 60%) was obtained as an oil.

[0749] Part E: The tetrahydropyranyl hydroxamate (855 mg, 1.26 mmol) was dissolved in absolute methanol (10 mL). Acetyl chloride (0.78 mL, 11 mmol) was added over 2-3 minutes. After 4 hours both tetrahydropyranyl groups had been cleaved. The reaction was concentrated, azeotroped with chloroform/acetonitrile, and dried in vacuo affording the title compound as a white foam (676 mg, 98%). MS (EI) MH⁺ calculated for C₂₁H₂₃F₃N₂O₇S: 505, found 505.

EXAMPLE 231 Preparation of N-hydroxy-4-[[4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0750]

[0751] Part A: To a solution of the compound of example N-tert-butoxycarbonyl-ethyl 4-(4-fluorophenylsulfonyl)-4-piperidinecarboxylate, hydrochloride of Preparative Example II (1.50 g, 3.61 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.94 g, 9.03 mmol) and (4-trifluoromethylthio) phenol (1.05 g, 5.41 mmol) and the solution was heated to 100 degrees Celsius for 24 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and dried over sodium sulfate. Filtration through silica gel (ethyl acetate) provided the phenoxyphenol compound as an oil (2.35 g, quantitative yield). MS(CI) MH⁺ calculated for C₂₆H₃₀NO₇S₂F₃: 590, found 590.

[0752] Part B: To a solution of phenoxyphenol compound of part A (2.35 g, <3.61 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added sodium hydroxide (1.44 g, 36.1 mmol) in water (5 mL). The solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated under a stream of nitrogen to remove the solvents and the residue was dissolved in water and acidified to pH=1 with 10% hydrochloric acid. The solution was extracted with ethyl acetate and washed with saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the carboxylic acid as an oil (2.0 g, quantitative yield).

[0753] Part C: To a solution of the carboxylic acid of part B (2.0 g, <3.61 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (586 mg, 4.33 mmol), 4-methylmorpholine (1.19 mL, 10.8 mmol) and O-tetrahydropyranyl hydroxylamine (634 mg, 5.41 mmol) and the solution was stirred for 30 minutes. The 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (969 mg, 5.05 mmol) was added and the solution was stirred for seven days. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as a clear, colorless oil (1.07 g, 45% yield). MS(CI) MNa⁺ calculated for C₂₉H₃₅N₂O₈S₂F₃: 683, found 683.

[0754] Part D: To a solution of the protected hydroxamate of part C (1.05 g, 1.60 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was diluted with ethyl ether and the resulting white precipitate was collected by vacuum filtration to provide the title compound as a white solid (330 mg, 40% yield). MS(CI) MH+calculated for C₁₉H₁₉N₂O₅S₂F₃: 477, found 477. HRMS calculated for C₁₉H₁₉N₂O₅S₂F₃: 477.0766, found 477.0766. Analytical calculation for C₁₉H₁₉N₂O₅S₂ HCl: C, 44.49; H, 3.93; N, 5.46; Cl, 6.91. Found: C, 44.51; H, 3.90; N, 5.38; Cl, 6.95.

EXAMPLE 232 Preparation of 1-[4-[[1-cyclopropyl-4-[(hydroxyamino)carbonyl]-4-piperidinyl] sulfonyl]phenyl]-N-methyl-N-(phenylmethyl)-4-piperidinecarboxamide, monohydrochloride

[0755]

[0756] Part A: To a solution of ethyl N-cyclopropyl-4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate (Preparative Example VI, Part A) (2.0 g, 5.11 mmol) in dimethylacetamide (10 mL) was added methyl isonipectotate (1.03 mL, 7.66 mmol) and cesium carbonate (4.16 g, 12.78 mmol) and was heated to one hundred ten degrees Celsius for 18 hours. The solution was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an oil (1.81 g, 74%). MS(CI) MH⁺ calculated for C₂₄H₃₄N₂O₆S: 479, found 479.

[0757] Part B: To a solution of the phenylamine of part A (1.79 g, 3.74 mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanoate (960 mg, 7.49 mmol) and the resulting solution was stirred for 18 hours at ambient temperature. The solution was concentrated in vacuo and the residue was dissolved into water. The solution was acidified with 3N hydrochloric acid to pH=3. The resulting precipitate was collected and washed with ethyl ether to provide the acid as a light yellow solid (1.09 g, 63%). MS(CI) MH⁺ calculated for C₂₃H₃₂N₂O₆S: 465, found 465.

[0758] Part C: To a solution of the acid of part B (500 mg, 1.08 mmol) in dichloromethane (10 mL) was added 1-hydroxybenzotriazole hydrate (160 mg, 1.19 mmol), triethylamine (0.15 mL, 1.19 mmol) and N-benzylmethylamine (0.33 mL, 2.38 mmol). After thirty minutes the 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added and the solution was stirred for 20 hours at ambient temperature. The solution was diluted with ethyl acetate and washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the amide as a white solid (480 mg, 78%). MS(CI) MH⁺ calculated for C₃₁H₄₁N₃O₅S: 568, found 568.

[0759] Part D: To a solution of the amide of part C (400 mg, 0.71 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (282 mg, 7.1 mmol) in water (3 mL). The solution was heated to sixty degrees Celsius for 24 hours. The solution was concentrated under a stream of nitrogen and the residue was diluted with water and acidified with 3N hydrochloric acid to pH=2. The solution was concentrated to provide the acid as a crude white solid which is used in the next step without further purification. MS(CI) MH⁺ calculated for C₂₉H₃₇N₅O₅S: 540, found 540.

[0760] Part E: To a solution of the crude acid of part D (<0.71 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (115 mg, 0.85 mmol), 4-methylmorpholine (0.39 mL) and O-tetrahydropyranyl hydroxylamine (124 mg, 1.06 mmol). After thirty minutes 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (190 mg, 0.99 mmol) was added and the solution was stirred for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the protected hydroxamate as an oil (184 mg, 41%). MS(CI) MH⁺ calculated for C₃₄H₄₆N₄O₆S: 0.639, found 639.

[0761] Part F: To a solution of the protected hydroxamate of part E (180 mg, 0.28 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for one hour. Trituration (ethyl ether) and vacuum filtration provided the title compound as a white solid (96.5 mg, 58%). MS(CI) MH⁺ calculated for C₂₉H₃₈N₄O₅S: 555, found 555. HRMS calc. 555.2641, found 555.2644.

EXAMPLE 233 Preparation of 4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, monohydrochloride

[0762]

[0763] Part A: To a solution of isonipecotic acid (5.8 g, 44.9 mmol) in water (200 mL) was added sodium carbonate (4.62 g, 44.9 mmol) followed by the drop-wise addition of di-tert-butyl-dicarbonate (10.1 g, 46.3 mmol) in dioxane (40 mL). After four hours the solvent was concentrated in vacuo and the solution was extracted with ethyl ether. The aqueous layer was acidified with 3N hydrochloric acid to pH=2. The solution was extracted with ethyl ether and the organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided N-Boc-isonipecotic acid as a white solid (9.34 g, 90%).

[0764] Part B: To a solution of the N-Boc-isonipecotic acid of part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.21 g, 89%).

[0765] Part C: To a solution of the amide of part B (1.20 g, 3.84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII,

[0766] Part A (956 mg, 2.56 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.92 g, 8.96 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an oil (1.53 g, 68%). MS(CI) MH⁺ calculated for C₃₀H₄₇N₃O₆S: 578, found 578.

[0767] Part D: To a solution of the phenylamine of part C (1.5 g, 2.6 mmol) in ethanol (9 mL) and tetrahydrofuran (9 mL) was added sodium hydroxide (1.02 g, 26 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=3 with 3N hydrochloric acid. Vacuum filtration provided the acid as a beige solid (500 mg, 33%). MS(CI) MH+calculated for C₂₈H₄₃N₃O₆S: 550, found 550.

[0768] Part E: To a solution of the acid of part D (492 mg, 0.84 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (136 mg, 1.01 mmol), 4-methylmorpholine (0.46 mL, 4.20 mmol), and O-tetrahydropyranyl hydroxylamine (147 mg, 1.26 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.18 mmol) was added and the solution was stirred for 72 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the protected hydroxamate as an oil (524 mg, 96%). MS(CI) MH⁺ calculated for C₃₃H₅₁N₄O₇S: 649, found 649.

[0769] Part F: To a solution of the protected hydroxamate of part E (514 mg, 0.79 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was concentrated in vacuo and trituration (ethyl ether) provided the title compound as a white solid (360 mg, 76%). MS(CI) MH+calculated for C₂₈H₄₄N₄O₆S: 565, found 565. HRMS calculated for C₂₈H₄₄N₄O₆S: 565.3060, found 565.3070. Analytical calculation for C₂₈H₄₄N₄O₆S 2 HCl:2H₂O: C, 49.92; H, 7.48; N, 8.32; S, 4.76; Cl, 10.52. Found: C, 49.41; H, 7.55; N, 7.85; S, 4.53; Cl, 10.78.

EXAMPLE 234 Preparation of 4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide

[0770]

[0771] Part A: A solution of the hydroxamate of Example 233, part F (50 mg, 0.08 mmol) in water (2 mL) was neutralized with saturated sodium bicarbonate. The aqueous solution was extracted with ethyl acetate. Concentration in vacuo provided the hydroxamate free base as an orange solid (35 mg, 75%).

EXAMPLE 235 Preparation of 1-[4-[[4[(hydroxyamino)-carbonyl]-1-(2-methoxyethyl)-4-piperidinyl]sulfonyl]phenyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-4-piperidine-carboxamide, dihydrochloride

[0772]

[0773] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxy-benzotriazole hydrate (620 mg, 4.59 mmol), 2-(2-methylaminoethyl)pyridine (0.69 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.03 g, 68%). MS(CI) MH⁺ calculated for C₁₉H₂₉N₃O₃: 348, found 348.

[0774] Part B: To a solution of the amide of part A (1.0 g, 2.88 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (716 mg, 1.92 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.20 g, 6.72 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (1.20 g, quantitative yield). MS(CI) MH⁺ calculated for C₃₁H₄₄N₄O₆S: 601, found 601.

[0775] Part C: To a solution of the phenylamine of part B (1.20 g, 2.00 mmol) in ethanol (8 mL) and tetrahydrofuran (8 mL) was added sodium hydroxide (800 mg, 20 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. Concentration in vacuo provided the crude acid as an oil. MS(CI) MH⁺ calculated for C₂₉H₄₀N₄O₆S: 573, found 573.

[0776] Part D: To a solution of the acid of part C (<2.0 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (324 mg, 2.04 mmol), 4-methylmorpholine (1.1 mL, 10.0 mmol), and O-tetrahydropyranyl hydroxylamine (351 mg, 3.00 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (536 mg, 2.80 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Reverse phase chromatography (on silica, acetonitrile/water) provided the protected hydroxamate as an oil (170 mg, 13% yield over two steps). MS(CI) MH⁺ calculated for C₃₄H₄₉N₅O₇S: 672, found 672.

[0777] Part E: To a solution of the protected hydroxamate of part D (160 mg, 0.24 mmol) in dioxane (7 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 30 minutes. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (90 mg, 57%). MS(CI) MH+calculated for C₂₉H₃₇N₅O₆S: 588, found 588. HRMS calculated for C₂₉H₃₇N₅O₆S: 558.2856, found 588.2857.

EXAMPLE 236 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[(phenylamino)-carbonyl]-1-piperidinyl]phenyl]-sulfonyl]-4-piperidinecarboxamide monohydrochloride)

[0778]

[0779] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (4 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (752 mg, 4.28 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.47 mL, 4.28 mmol) was added. After two hours aniline (0.39 mL, 4.28 mmol) was added and the solution was stirred for 20 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (1.48 g, quantitative yield).

[0780] Part B: To a solution of the amide of part A (1.48 g, 4.28 mmol) in dichloromethane (5 mL) was added trifluoroacetic (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (1.06 mg, 2.85 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.25 g, 9.97 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (1.74 g, quantitative yield). MS(CI) MH⁺ calculated for C₂₉H₃₉N₃O₆S: 558, found 558.

[0781] Part C: To a solution of the phenylamine of part B (1.74 g, 2.85 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.14 g, 28.5 mmol) in water (7 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (1.62 g, quantitative yield). MS(CI) MH⁺ calculated for C₂₇H₃₅N₃O₆S: 530, found 530.

[0782] Part D: To a solution of the acid of part C (1.60 g, 2.83 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (458 mg, 3.40 mmol), 4-methylmorpholine (1.56 mL, 14.2 mmol), and O-tetrahydropyranyl hydroxylamine (497 mg, 4.24 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (759 mg, 3.96 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (790 mg, 44%). MS(CI) MH⁺ calculated for C₃₂H₄₄N₄O₇S: 629, found 629.

[0783] Part E: To a solution of the protected hydroxamate of part D (780 mg, 1.24 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (580 mg, 80%). MS(CI) MH+calculated for C₂₇H₃₆N₄O₆S: 545, found 545. HRMS calculated for C₂₇H₃₆N₄O₆S: 545.2434, found 545.2429.

EXAMPLE 237 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[(3-phenyl-propyl)amino]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride

[0784]

[0785] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol), 3-phenyl-1-propylamine (0.72 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 18 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a yellow oil (1.4 g, 93%).

[0786] Part B: To a solution of the amide of part A (1.4 g, 4.05 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. The resulting solid was collected by vacuum filtration and washed with ethyl ether. The solid was added to a solution of the compound of Preparative Example VII, Part A (1.01 mg, 2.70 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.07 g, 9.45 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.71 g, quantitative yield). MS(CI) MH⁺ calculated for C₃₂H₄₅N₃O₆S: 600, found 600.

[0787] Part C: To a solution of the phenylamine of part B (1.70 g, 2.70 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.08 g, 27.0 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a white solid (1.15 g, 75%). MS(CI) MH⁺ calculated for C₃₀H₄₁N₃O₆S: 572, found 572.

[0788] Part D: To a solution of the acid of part C (1.02 g, 1.68 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (272 mg, 2.02 mmol), 4-methylmorpholine (0.92 mL, 8.4 mmol), and O-tetrahydropyranyl hydroxylamine (295 mg, 2.52 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (451 mg, 2.35 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as an oil (490 mg, 41%). MS(CI) MH⁺ calculated for C₃₅H₅₀N₄O₇S: 671, found 671.

[0789] Part E: To a solution of the protected hydroxamate of part D (480 mg, 0.72 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for one hour. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (400 mg, 90%). MS(CI) MH⁺ calculated for C₃₀H₄₂N₄O₆S: 587, found 587. Analytical calculation for C₃₀H₄₂N₄O₆S 2HCl :2H₂O: C, 51.79; H, 6.95; N, 8.05; S, 4.61; Cl, 10.19. Found: C,51.34; H, 6.72; N, 7.82; S, 4.59; Cl, 10.92.

EXAMPLE 238 Preparation of rel-4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride

[0790]

[0791] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.4 g, quantitative yield).

[0792] Part B: To a solution of the amide of part A (1.4 g, 4.49 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided a solid that was added directly to a solution of the compound of Preparative Example II, Part D, (1.24 mg, 2.99 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.42 g, 10.5 mmol) was added and the solution was heated to one hundred degrees Celsius for 20 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow solid (1.90 g, quantitative yield). MS(CI) MH⁺ calculated for C₃₂H₄₉N₃O₇S: 620, found 620.

[0793] Part C: To a solution of the phenylamine of part B (1.9 g, 3.0 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.2 g, 30 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. The solution was extracted with ethyl acetate and washed with 1M hydrochloric acid and saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the acid as a yellow oil (1.9 g, quantitative yield). MS(CI) MH⁺ calculated for C₃₀H₄₅N₃O₇S: 592, found 592.

[0794] Part D: To a solution of the acid of part C (1.87 g, 3.00 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (486 mg, 3.6 mmol), 4-methylmorpholine (1.65 mL, 15 mmol), and O-tetrahydropyranyl hydroxylamine (526 mg, 4.5 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (805 mg, 4.2 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as an oil (1.63 g, 79%).

[0795] Part E: To a solution of the protected hydroxamate of part D (1.61 g, 2.33 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 45 minutes. The solution was concentrated in vacuo and trituration (ethyl ether) a white solid. Reverse phase chromatography (on silica, acetonitrile/water(hydrochloric acid)) produced fractions A, B, C and D. Concentration in vacuo of fraction A provided the title compound as a white solid (59 mg). MS(CI) MH⁺ calculated for C₂₅H₃₈N₄O₅S: 507, found 507.

EXAMPLE 239 Preparation of rel-1,1-dimethylethyl 4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate

[0796]

[0797] Part A: From the reverse phase chromatography of Example 238, Part E, fraction C was concentrated in vacuo to provide the title compound as a white solid (49 mg). MS(CI) MH⁺ calculated for C₃₀H₄₆N₄O₇S: 607, found 607.

EXAMPLE 240 Preparation of rel-4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride

[0798]

[0799] Part A: From the reverse phase chromatography of Example 238, Part E, fraction B was concentrated in vacuo to provide the title compound as a white solid (198 mg). MS(CI) MH⁺ calculated for C₂₅H₃₈N₄O₅S: 507, found 507.

EXAMPLE 241 Preparation of rel-1,1-dimethylethyl 4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate

[0800]

[0801] Part A: From the reverse phase chromatography of Example 238, Part E, fraction D was concentrated in vacuo to provide the title compound as a white solid (242 mg). MS(CI) MH+calculated for C₃₀H₄₆N₄O₇S: 607, found 607.

EXAMPLE 242 Preparation of 4-[[4-[4-[[(2,3-dihydro-1H-inden-2-yl)amino]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidine-carboxamide, monohydrochloride

[0802]

[0803] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 2-aminoindane hydrochloride (853 mg, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a white solid (1.35 g, 90%).

[0804] Part B: To a solution of the amide of part A (1.35 g, 3.92 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided a solid which was added directly to a solution of the title compound of Preparative Example VII, Part A, (976 mg, 2.61 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.97 g, 9.14 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.65 g, quantitative yield). MS(CI) MH⁺ calculated for C₃₂H₄₃N₃O₆S: 598, found 598.

[0805] Part C: To a solution of the phenylamine of part B (1.60 g, 2.61 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.04 g, 26 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 18 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=3 with 3N hydrochloric acid. Vacuum filtration provided the acid as a beige solid (1.06 g, 71%). MS(CI) MH⁺ calculated for C₃₀H₃₉N₃O₆S: 570, found 570.

[0806] Part D: To a solution of the acid of part E (1.0 g, 1.65 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (267 mg, 1.98 mmol), 4-methylmorpholine (0.91 mL, 8.25 mmol), and O-tetrahydropyranyl hydroxylamine (289 mg, 2.48 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (443 mg, 2.31 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate, methanol) provided the protected hydroxamate as an oil (575 mg, 52%). MS(CI) MH⁺ calculated for C₃₅H₄₈N₄O₇S: 669, found 669.

[0807] Part E: To a solution of the protected hydroxamate of part D (565 mg, 0.85 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was concentrated in vacuo and trituration (ethyl ether) provided the title compound as a white solid (450 mg, 86%). MS(CI) MH⁺ calculated for C₃₀H₄₀N₄O₆S: 585, found 585. HRMS calculated for C₃₀H₄₀N₄O₆S: 585.2747, found 585.2776. Analytical calculation for C₃₀H₄₀N₄O₆S 2HCl :2H₂O: C, 51.94; H, 6.68; N, 8.08; S, 4.62; Cl, 10.22. Found: C, 51.66; H, 6.25; N, 7.80; S, 4.73; Cl, 10.33.

EXAMPLE 243 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-[(phenylamino)carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0808]

[0809] Part A: To a solution of the product of Example 232, Part B (562 mg, 1.12 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (164 mg, 0.93 mmol) and 4-methylmorpholine (0.21 mL, 1.87 mmol). The solution was stirred for 45 minutes and aniline (0.085 mL, 0.93 mmol) was added. The solution was stirred for 72 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as an oil (434 mg, 86%). MS(CI) MH+calculated for C₂₉H₃₇N₃O₅S: 540, found 540.

[0810] Part B: To a solution of the amide of part A (425 mg, 0.79 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (315 mg, 7.89 mmol) in water (2 mL) and the solution was heated to sixty degrees Celsius for 18 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (261 mg, 60%). MS(CI) MH⁺ calculated for C₂₇H₃₃N₃O₅S: 512, found 512.

[0811] Part C: To a solution of the acid of part B (245 mg, 0.45 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (73 mg, 0.54 mmol), 4-methylmorpholine (0.25 mL, 2.25 mmol), and O-tetrahydropyranyl hydroxylamine (79 mg, 0.68 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the protected hydroxamate as a yellow oil (242 mg, 88%). MS(CI) MH⁺ calculated for C₃₂H₄₂N₄O₆S: 611, found 611.

[0812] Part D: To a solution of the protected hydroxamate of part C (235 mg, 0.38 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (114 mg, 53%). MS(CI) MH⁺ calculated for C₂₇H₃₄N₄O₅S: 527, found 527. HRMS calculated for C₂₇H₃₄N₄O₅S: 527.2328, found 527.2339.

EXAMPLE 244 Preparation of 1-[4-[[4-[(hydroxyamino)-carbonyl]-1-(2-methoxyethyl)-4-piperidinyl]-sulfonyl]phenyl]-N-methyl-N-phenyl-4-piperidinecarboxamide, monohydrate

[0813]

[0814] Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (500 mg, 2.18 mmol) in dichloromethane (2 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (319 mg, 1.82 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.20 mL, 1.82 mmol) was added. After two hours, N-methylaniline (0.20 mL, 1.82 mmol) was added and the solution was stirred for 20 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (445 mg, 77%).

[0815] Part B: To a solution of the amide of part A (440 g, 1.38 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (344 mg, 0.92 mmol) in dimethylacetamide (10 mL). Cesium carbonate (1.05 g, 3.22 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (440 mg, 84%).

[0816] Part C: To a solution of the phenylamine of part B (440 mg, 0.77 mmol) in ethanol (7 mL) and tetrahydrofuran (7 mL) was added sodium hydroxide (308 mg, 7.7 mmol) in water (3 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a yellow solid and carried on to the next step without additional purification.

[0817] Part D: To a solution of the acid of part C (<0.77 mmol) in N,N-dimethylformamide (10 mL) was added-1-hydroxybenzotriazole hydrate (125 mg, 0.92 mmol), 4-methylmorpholine (0.43 mL, 3.85 mmol), and O-tetrahydropyranyl hydroxylamine (135 mg, 1.16 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (207 mg, 1.08 mmol) was added and the solution was stirred for 24 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (150 mg, 30%). MS(CI) MH⁺ calculated for C₃₃H₄₆N₄O₇S: 643, found 643.

[0818] Part E: To a solution of the protected hydroxamate of part D (150 mg, 0.23 mmol) in dioxane (2 mL) was added 4M hydrochloric acid in dioxane (3 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a yellow solid (75 mg, 55%). MS(CI) MH⁺ calculated for C₂₈H₃₈N₄O₆S: 559, found 559. HRMS calculated for C₂₈H₃₈N₄O₆S: 559.2590, found 559.2613.

EXAMPLE 245 Preparation of 1-acetyl-N-hydroxy-4-[[4-[4-[(phenylamino)carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide

[0819]

[0820] Part A: To a solution of the N-Boc-amide of Preparative Example III, Part B, (6.9 g, 11.4 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example II, Part D (3.15 g, 7.6 mmol) in dimethylacetamide (30 mL). Cesium carbonate (8.65 g, 26.6 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a tan solid (3.92 g, 86%).

[0821] Part B: To a solution of the phenylamine of part A (3.90 g, 6.51 mmol) in methanol (20 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 3 hours. Concentration in vacuo followed by trituration (ethyl ether) provided the amine hydrochloride salt as a yellow solid (3.25 g, 93%).

[0822] Part C: To a solution of the amine hydrochloride salt of part B (500 mg, 0.93 mmol) in dichloromethane (5 mL) was added triethylamine (0.40 mL, 2.79 mmol) followed by acetyl chloride (0.07 mL, 1.02 mmol). The solution was stirred for 3 hours. The solution was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the acylated compound as an oil (390 mg, 77%). MS(CI) MH⁺ calculated for C₂₈H₃₅N₃O₆S: 542, found 542.

[0823] Part D: To a solution of the acylated compound of part C (390 mg, 0.72 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (58 mg, 1.44 mmol) in water (1 mL) and the solution was heated to sixty degrees Celsius for 3 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. The solution was extracted with ethyl acetate and washed with water and saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the acid as a white solid (137 mg, 37%). MS(CI) MH⁺ calculated for C₂₆H₃₁N₃O₆S: 514, found 514.

[0824] Part E: To a solution of the acid of part D (137 mg, 0.27 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added 1-hydroxybenzotriazole hydrate (44 mg, 0.32 mmol), 4-methylmorpholine (0.10 mL, 1.08 mmol), and O-tetrahydropyranyl hydroxylamine (47 mg, 0.41 mmol). After one hour 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol) was added and the solution was stirred for 24 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a white solid (140 mg, 85%). MS(CI) MH⁺ calculated for C₃₁H₄₀N₄O₇S: 613, found 613.

[0825] Part F: To a solution of the protected hydroxamate of part E (130 mg, 0.21 mmol) in dioxane (2 mL) was added 4M hydrochloric acid in dioxane (3 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a yellow solid (51 mg, 48%). MS(CI) MH⁺ calculated for C₂₆H₃₂N₄O₆S: 528, found 528.

EXAMPLE 246 Preparation of 4-[[4-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, monohydrate

[0826]

[0827] Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B (750 mg, 3.27 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours, indoline (0.36 mL, 3.21 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (940 mg, 89%).

[0828] Part B: To a solution of the amide of part A (935 g, 2.83 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A, (705 mg, 1.89 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.15 g, 6.61 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (893 mg, 81%). MS(CI) MH⁺ calculated for C₃₁H₄₁N₃O₆S: 584, found 584.

[0829] Part C: To a solution of the phenylamine of part B (885 g, 1.52 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (607 mg, 15.2 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (475 g, 53%). MS(CI) MH⁺ calculated for C₂₉H₃₇N₃O₆S: 556, found 556.

[0830] Part D: To a solution of the acid of part C (465 g, 0.79 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (128 mg, 0.95 mmol), 4-methylmorpholine (0.43 mL, 3.95 mmol), and O-tetrahydropyranyl hydroxylamine (139 mg, 1.18 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (212 mg, 1.10 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (305 mg, 60%). MS(CI) MH⁺ calculated for C₃₄H₄₆N₄O₇S: 655, found 655.

[0831] Part E: To a solution of the protected hydroxamate of part D (300 mg, 0.46 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (5 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (260 mg, 94%). MS(CI) MH⁺calculated for C₂₉H₃₄N₄O₆S: 571, found 571.

EXAMPLE 247 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[(phenylmethyl) amino]carbonyl]-1-piperidinyl]phenyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0832]

[0833] Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B, (750 mg, 3.27 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (640 mg, 3.34 mmol), 1-hydroxybenzotriazole hydrate (463 mg, 3.43 mmol) and diisopropylethylamine (1.25 mL, 7.19 mmol). After thirty minutes, benzylamine (0.41 mL, 3.76 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as an oil (320 mg, 31%).

[0834] Part B: To a solution of the amide of part A (320 g, 1.0 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example II, Part D, (288 mg, 0.77 mmol) in dimethylacetamide (10 mL). Cesium carbonate (878 g, 2.7 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (367 mg, 83%). MS(CI) MH⁺ calculated for C₃₀H₄₁N₃O₆S: 572, found 572.

[0835] Part C: To a solution of the phenylamine of part B (367 g, 0.64 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (257 mg, 6.4 mmol) in water (2 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (415 g, quantitative yield). MS(CI) MH⁺calculated for C₂₈H₃₇N₃O₆S: 544, found 544.

[0836] Part D: To a solution of the acid of part C (415 g, <0.64 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (104 mg, 0.77 mmol), 4-methylmorpholine (0.35 mL, 3.20 mmol), and O-tetrahydropyranyl hydroxylamine (112 mg, 0.96 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (172 mg, 0.90 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (9 mg, 2%). MS(CI) MH⁺ calculated for C₃₃H₄₆N₄O₇S: 643, found 643.

[0837] Part E: To a solution of the protected hydroxamate of part D (9 mg, 0.014 mmol) in dioxane (1 mL) was added 4M hydrochloric acid in dioxane (1 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (2.5 mg, 30%). MS(CI) MH⁺ calculated for C₂₈H₃₄N₄O₆S: 559, found 559.

EXAMPLE 248 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-[[[4-(trifluoromethoxy)-phenyl]amino]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride

[0838]

[0839] Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B, (750 mg, 3.27 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours, 4-(trifluoromethoxy)aniline (0.43 mL, 3.21 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (1.16 g, 93%).

[0840] Part B: To a solution of the amide of part A (1.16 g, 2.99 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example VII,

[0841] Part A (743 mg, 1.99 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.26 g, 6.90 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.38 g, quantitative yield). MS(CI) MH⁺ calculated for C₃₀H₃₈N₃O₇SF₃: 642, found 642.

[0842] Part C: To a solution of the phenylamine of part B (1.38 g, 2.00 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (800 mg, 20 mmol) in water (5 mL), and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (536 g, 41%). MS(CI) MH⁺ calculated for C₂₈H₃₄N₃O₇SF₃: 614, found 614.

[0843] Part D: To a solution of the acid of part C (536 g, 0.83 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (134 mg, 0.99 mmol), 4-methylmorpholine (0.46 mL, 4.15 mmol), and O-tetrahydropyranyl hydroxylamine (145 mg, 1.24 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (223 mg, 1.16 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (287 mg, 48%). MS(CI) MH⁺ calculated for C₃₃H₄₃N₄O₈SF₃: 713, found 713.

[0844] Part E: To a solution of the protected hydroxamate of part D (280 mg, 0.39 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (228 mg, 88%). MS(CI) MH⁺ calculated for C₂₈H₃₅N₄O₇SF₃: 629, found 629.

EXAMPLE 249 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[[3-(trifluoro-methoxy)phenyl]amino]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0845]

[0846] Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B, (750 mg, 3.27 mmol) in dichloromethane (3 mL) was ,added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours 3-(trifluoromethoxy)-aniline (0.43 mL, 3.21 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (1.20 g, 97%).

[0847] Part B: To a solution of the amide of part A (1.20 g, 3.10 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example VII, Part A, (770 mg, 2.06 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.34 g, 7.21 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.72 g, quantitative yield). MS(CI) MH⁺ calculated for C₃₀H₃₈N₃O₇SF₃: 642, found 642.

[0848] Part C: To a solution of the phenylamine of part B (1.72 g, <2.06 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (824 mg, 20.6 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 18 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. Concentration in vacuo provided the acid as a crude brown oil which was used in the next step without additional purification.

[0849] Part D: To a solution of the acid of part C (<2.06 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (334 mg, 2.47 mmol), 4-methylmorpholine (1.13 mL, 10.3 mmol), and O-tetrahydropyranyl hydroxylamine (361 mg, 3.09 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (64 mg, 4% for 2 steps). MS(CI) MH⁺ calculated for C₃₃H₄₃N₄O₈SF₃: 713, found 713.

[0850] Part E: To a solution of the protected hydroxamate of part-D (63 mg, 0.089 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (5 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (48 mg, 81%). MS(CI) MH⁺ calculated for C₂₈H₃₅N₄O₇SF₃: 629, found 629.

EXAMPLE 250 Preparation of 1-(2-ethoxyethyl)-N-hydroxy-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monohydrochloride

[0851]

[0852] Part A: To a solution of the product of Preparative Example II, Part D, (1.0 g, 2.4 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.99 g, 7.2 mmol) in N,N-dimethylformamide (5 mL) was added 2-bromoethyl ethyl ether (0.33 mL, 2.87 mmol) and the solution was stirred at ambient temperature for 36 hours. Then N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo provided the ethoxyl ethyl amine as a light yellow gel (0.68 g, 65.4%).

[0853] Part B: To a solution of ethoxyl ethyl amine (0.68 g, 1.56 mmol) of part A and powdered potassium carbonate (0.43 g, 3.1 mmol) in N,N-dimethylformamide (5 mL) was added 4-(trifluoromethoxy)phenol (0.4 mL, 3.08 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided the desired trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (1.0 g, quantitative).

[0854] Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of Part B (1.0 g, 1.72 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was added sodium hydroxide (0.688 g, 17.2 mmol) in water (4 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH=2. Vacuum filtration of the white precipitate provided the acid as a white solid (0.94 g, quantitative yield).

[0855] Part D: To a solution of the acid of part C (0.94 g, 1.86 mmol), N-methyl morpholine (0.61 mL, 5.55 mmol), 1-hydroxybenzotriazole (0.76 g, 5.59 mmol) and O-tetrahydropyranyl hydroxylamine (0.33 g, 2.7 mmol) in N,N-dimethylformamide (40 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.06 g, 5.59 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.74 g, 66.1%).

[0856] Part E: To a solution of 4N hydrochloric acid (3 mL, 12 mmol)) in dioxane was added a solution of the tetrahydropyranyl amide of part D (0.74 g, 1.2 mmol) in methanol (0.4 ml) and dioxane (1.2 mL) and was stirred at ambient temperature for 3 hours. Filtration of precipitation gave the title compound as white solid (0.217 g, 32.9%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃.HCl.0.5H₂O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.

EXAMPLE 251 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide monomethane-sulfonate (salt)

[0857]

[0858] Part A: To the ethanol solution of the product of Preparative Example VII, Part D, (0.3 g, 0.5 mmol) was added methane sulfonic acid (0.042 mL, 0.65 mmol). After two hours stirring at room temperature the solution was cooled to zero degree Celsius. Filtration of the precipitate gave the title compound as a white crystalline solid (0.105 g, 35%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃. CH₄O₃S. H₂O: C, 43.67; H, 4.94; N, 4.43. Found: C, 43.96; H, 4.62; N, 4.47.

EXAMPLE 252 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide

[0859]

[0860] Part A: The title compound of Preparative Example VII (15 g, 27 mmol) was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, water, brine and dried over magnesium sulfate. Concentration in vacuo and recrystallization from hot toluene gave the title compound as white crystals (13.14 g, 93.9%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃: C, 50.96; H, 4.86; N, 5.40; S, 6.18. Found: C, 51.33; H, 5.11; N, 5.29; S, 6.50.

EXAMPLE 253 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methyl-benzenesulfonate) (salt)

[0861]

[0862] Part A: To the ethanol solution of Preparative Example VII (8 g, 13.32 mmol) was added p-toluenesulfonic acid (2.9 g, 15.24 mmol) and the solution was stirred at ambient temperature for 6 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as white crystals (6.58 g, 71.8%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃.C₇H₈SO₃: C, 50.43; H, 4.82; N, 4.06; S, 9.28. Found: C, 50.36; H, 4.95; N, 4.00; S, 9.47.

EXAMPLE 254 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide sulfate (2:1) (salt)

[0863]

[0864] Part A: To a solution of Preparative Example VII (0.35 g, 0.58 mmol) in ethanol (1.5 mL) was added sulfuric acid (17 ?L, 0.32 mmol) and the solution was stirred at ambient temperature for 6 hours. Evaporation of solvent and recrystallization from hot acetonitrile gave the title compound as a white powder (180 mg, 54.6%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃.0.7H₂SO₄: C, 45.00; H, 4.53; N, 4.77; S, 9.28. Found: C, 44.77; H, 4.97; N, 4.41; S, 9.19.

EXAMPLE 255 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide phosphate (1:1) (salt)

[0865]

[0866] Part A: To the ethyl acetate solution (4 mL) of Example 252 (0.5 g, 0.9 mmol) was added concentrated phosphoric acid (85%, 0.1248 g, 1.08 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as a white powder (0.4917 g, 82.7%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃.H₃PO₄.H₂O: C, 41.64; H, 4.77; N, 4.42. Found: C, 41.14; H, 4.64; N, 4.25.

EXAMPLE 256 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monoacetate (salt)

[0867]

[0868] Part A: To a solution of Example 252 (0.5 g, 0.9 mmol) in ethyl acetate (5 mL) was added concentrated acetic acid (63.7 mg, 1.08 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethyl acetate gave the title compound as a white crystalline solid (0.4635 g, 83.0%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃.0.7C₂H₄O₂: C, 50.14; H, 5.00; N, 5.00; S, 5.72. Found: C, 50.47; H, 5.09; N, 5.00; S, 6.13.

EXAMPLE 257 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide 2-hydroxy-1,2,3-propanetri-carboxylate (3:1) (salt)

[0869]

[0870] Part A: To a solution of Example 252 (0.3 g, 0.578 mmol) in ethyl acetate (5 mL) was added citric acid (41 mg, 0.21 mmol) and the solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as a white crystalline solid (0.181 g, 53.7%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃.(⅓)C₆H₉O₇. 0.9H₂O: C, 48.34; H, 4.99; N, 4.70; S, 5.38. Found: C, 48.42; H, 4.99; N, 4.70; S, 5.38.

EXAMPLE 258 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monobenzenesulfonate (salt)

[0871]

[0872] Part A: To a solution of Preparative Example VII, Part D (0.4 g, 0.66 mmol) in ethanol (2.5 mL) was added benzene sulfonic acid (0.11 g, 0.69 mmol) and the solution was stirred at ambient temperature for 3 hours. Evaporation of the solvent and recrystallization from hot ethanol at minus 20 degrees Celsius gave the title compound as white crystals (0.28 g, 64.3%). Analytical calculation for C₂₂H₂₅N₂07SF₃.C₆H₆SO₃.0.2H₂O: C, 49.44; H, 4.65; N, 4.12; S, 9.43. Found: C, 49.18; H, 4.67; N, 4.08; S, 9.75.

EXAMPLE 259 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide (2R,3R)-2,3-dihydroxy-butanedioate (2:1) (salt)

[0873]

[0874] Part A: To a solution of Example 252 (0.3 g, 0.578 mmol) in ethyl acetate (5 mL) was added tartaric acid (48 mg, 0.3 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol at zero degrees Celsius gave the title compound as a white solid (0.2 g, 58.3%). Analytical calculation for C₂₂H₂₅N₂O₇SF₃.0.5C₄H₆O₆. 1.25H₂O: C, 46.79; H, 4.99; N, 4.55; S, 5.20. Found: C, 47.17; H, 5.20; N, 4.07; S, 5.03

Example 260 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide phosphate (3:1) (salt)

[0875]

[0876] Part A: To a solution of Example 252 (0.5 g, 0.9 mmol) in ethyl acetate (5 mL) was added phosphoric acid (37 mg, 0.32 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol at zero degrees Celsius gave the title compound as a white solid (0.312 g, 59%). Analytical calculation for C₂₂H₂₅N₂07SF₃.0.33H₃PO₄. 0.5H₂O: C, 47.18; H, 4.86; N, 5.00. Found: C, 47.15; H, 4.73; N, 4.90.

EXAMPLE 261 Preparation of N-hydroxy-1-[2-(1H-imidazol-1-yl)ethyl]-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl] sulfonyl]-4-piperidinecarboxamide, dihydrochloride

[0877]

[0878] Part A: The aryl ether from Example 230, Part B (3.12 g, 5.2 mmol) was dissolved in absolute methanol (50 mL). Acetyl chloride (2.1 mL, 30 mmol) was added over 1 minute. The reaction was stirred for 4 hours, concentrated, azeotroped with chloroform/acetonitrile, and dried in vacuo, affording the desired hydroxyethyl compound as a white solid (2.75 g, 96%). The desired hydroxyethyl product was characterized by NMR spectroscopy.

[0879] Part B: To the dichloromethane solution of the hydroxyethyl compound of Part A (1 g, 1.9 mmol) was added thionyl chloride (3.8 mmol) and reaction solution was stirred at ambient temperature for 12 hours. Concentration in vacuo provided the chloride as a light yellow gel. To the solution of the chloride and potassium carbonate (0.54 g, 3.8 mmol) in N,N-dimethylformamide (5 mL) was added imidazole (0.4 g, 5.7 mmol) and solution was stirred at ambient temperature for 12 hours. Then N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the imidazole ethyl ester as a light yellow gel (0.82 g, 75.2%).

[0880] Part C: To a solution of imidazole ethyl ester of part A (0.82 g, 1.44 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.57 g, 14.4 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue to pH=1 and concentration in vacuo gave the carboxylic acid as the product. To a solution of the carboxylic-acid, N-methyl morpholine (0.62 mL, 5.7 mmol), 1-hydroxybenzotriazole (0.59 g, 4.3 mmol) and O-tetrahydropyranyl hydroxylamine (0.34 g, 2.9 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.83 g, 5.7 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.27 g, 29.7%).

[0881] Part D: To a solution of 4N hydrochloric acid in dioxane (2 mL, 8 mmol)) was added a solution of the tetrahydropyranyl amide of part B (0.27 g, 0.45 mmol) in methanol (1 ml) and 1,4-dioxane (3 mL) and was stirred at ambient temperature for 3 hours. Evaporation of solvent and trituration with ethyl ether gave the title compound as a white solid (0.179 g, 67%). Analytical calculation for C₂₄H₂₅N₄O₆SF₃.2HCl.1.25H₂O: C, 44.35; H, 4.57; N, 8.62. Found: C, 44.57; H, 4.36; N, 7.95.

EXAMPLE 262 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide trihydrochloride

[0882]

[0883] Part A: To a solution of the product of Preparative Example II, Part D, (1.5 g, 3.6 mmol) and powdered potassium carbonate (0.99 g, 7.2 mmol) in N,N-dimethylformamide (10 mL) was added 4-(1,2,4-triazole-1-yl)phenol (0.87 g, 5.4 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 32 hours. Solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided the N-Boc diaryl ether as a light yellow gel (0.907 g, 44.5%).

[0884] Part B: To a solution of N-Boc diaryl ether of part A (0.907 g, 1.6 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.44 g, 3.2 mmol) in N,N-dimethylformamide (5 mL) was added 2-bromoethyl methyl ether (0.36 mL, 3.8 mmol) and solution was stirred at ambient temperature for 36 hours. The N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo provided the methoxyl ethyl amine as a light yellow gel (0.82 g, 91%).

[0885] Part C: To a solution of the methoxyl ethyl amine of part B (0.80 g, 1.4 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.56 g, 14 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue until the pH=1 and concentration in vacuo gave the carboxylic acid as product. To a solution of the carboxylic acid, N-methyl morpholine (0.92 mL, 8.4 mmol), 1-hydroxybenzotriazole (0.57 g, 4.3 mmol) and O-tetrahydropyranyl hydroxylamine (0.34 g, 2.9 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.80 g, 4.2 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.39 g, 47.6%).

[0886] Part D: To a solution of 4N hydrochloric acid in dioxane (1.6 mL, 6.4 mmol)) was added a solution of the tetrahydropyranyl amide of part C (0.39 g, 0.66 mmol) in methanol (2 ml) and dioxane (6 mL) and was stirred at ambient temperature for 3 hours. Evaporation of the solvent and trituration with ethyl ether gave the title compound as a white solid (0.34 g, 83%). ESI MS calculated for C₂₃H₂₇N₅O₆S: 501, found 501.

EXAMPLE 263 Preparation of 1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide monohydrochloride

[0887]

[0888] Part A: To a methanol solution of the product of Example 253 (1.0 g, 1.4 mmol) and 20% palladium on carbon (1.5 g) was added ammonium formate (2.4 g, 38 mmol) and reaction solution was heated to reflux for 72 hours. The reaction solution was filtered through Celite and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on a C-18 reverse phase column eluting with acetonitrile/water with hydrochloric acid provided the title compound as a white powder (181 mg, 23.2%). Analytical calculation for C₂₂H₂₅N₂O₆SF₃.HCl: C, 49.03; H, 4.86; N, 5.20. Found: C, 48.80; H, 4.93; N, 5.29.

EXAMPLE 264 Preparation of N-hydroxy-1-[3-(4-morpholinyl)propyl]-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl] sulfonyl]-4-piperidinecarboxamide dihydrochloride

[0889]

[0890] Part A: To a solution of the product of Preparative Example II, Part D, (15 g, 36 mmol) and powdered potassium carbonate (10 g, 72 mmol) in N,N-dimethylformamide (200 mL) was added 4-(trifluoromethoxy)phenol (19.3 mL, 72 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (20 g, quantitative).

[0891] Part B: To a solution of trifluoromethoxyl phenoxyphenyl sulfone (1.0 g, 1.75 mmol) of part A in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.48 g, 3.5 mmol) in N,N-dimethylformamide (10 mL) was added morpholino propyl chloride (0.68 g, 3.5 mmol) and solution was stirred at 40 degree Celsius for 36 hours. The N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo provided the morpholino propyl amine as a light yellow gel (1 g, quantitative yield).

[0892] Part C: To a solution of morpholino propyl amine of part B (1 g, 1.6 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.67 g, 16 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue to pH=1 and concentration in vacuo gave the carboxylic acid as the product. To a solution of the carboxylic acid, N-methyl morpholine (0.18 mL, 4.8 mmol), 1-hydroxybenzotriazole (0.45 g, 3.2 mmol) and O-tetrahydropyranyl hydroxylamine (0.3 g, 2.5 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.64 g, 3.2 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.56 g, 50%).

[0893] Part D: To a solution of 4N hydrogen chloride in dioxane (2 mL, 8 mmol)) was added a solution of the tetrahydropyranyl amide of part C (0.56 g, 0.83 mmol) in methanol (3 ml) and dioxane (8 mL) and was stirred at ambient temperature for 3 hours. Evaporation of solvent and tritration with ethyl ether gave the title compound as a white solid (0.476 g, 86.5%). Analytical calculation for C₂₆H₃₂N₃O₇SF₃.2HCl: C, 47.28; H, 5.19; N, 6.36; S, 4.85. Found: C, 46.86; H, 5.35; N, 6.29; S, 5.09.

EXAMPLE 265 Preparation of N-hydroxy-1-(1H-imidazol-2-ylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy] phenyl]-sulfonyl]-4-piperidinecarboxamide dihydrochloride

[0894]

[0895] Part A: To a suspension of the hydrochloride salt from Preparative Example VIII, Part F, (0.988 g, 21.6 mmol) and 2-imidazolecarboxaldehyde (315 mg, 3.28 mmol) in methanol (5 mL) at room temperature was added borane-pyridine complex (0.41 mL, 3.28 mmol). After 18 hours the reaction was concentrated under a stream of nitrogen. Saturated aqueous sodium bicarbonate was then added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine and dried over sodium sulfate. Concentration gave a residue which was purified on silica gel eluting with ammonia-saturated methanol/methylene chloride (3/97) to afford the desired 4(5)-imidazole derivative (1.04 g, 89.7%) as a yellow solid. MS MH⁺ calculated for C₂₅H₂₆N₃O₅SF₃: 538, found 538.

[0896] Part B: A solution of sodium hydroxide (766 mg, 19.2 mmol) in water (5 mL) was added to a solution of the 4(5)-imidazole derivative of Part A (1.03 g, 1.92 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) and the resulting solution was stirred at ambient temperature for 66 hours. The solution was concentrated in vacuo to afford a residue which was treated with 2 N aqueous hydrochloric acid (14.4 mL, 28.8 mmol). Concentration afforded the desired carboxylic acid as a yellow foam which was used directly without purification.

[0897] Part C: To a solution of the carboxylic acid of

[0898] Part B in dimethylformamide (15 mL) was added sequentially N-methylmorpholine (1.16 g, 11.5 mmol), N-hydroxybenzotriazole (311 mg, 2.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (478 mg, 2.50 mmol), and O-tetrahydropyranyl hydroxylamine (303 mg, 2.6 mmol). After 16 hours at ambient temperature the reaction was warmed to 51 degrees Celsius for 2 hours and then concentrated in vacuo. Water was added and the mixture was extracted sequentially with ethyl acetate and with methylene chloride. The combined organic extracts were washed with brine and dried over sodium sulfate. Concentration gave a residue which was chromatographed on silica gel eluting with ammonia-saturated methanol/methylene chloride (7/93) to afford the desired tetrahydropyranyl-protected hydroxamate (0.50 g, 43%) as an off-white foam. MS MH+calculated for C₂₈H₃₁F₃N₄O₆S: 609, found 609.

[0899] Part D: To a solution of tetrahydropyranyl-protected hydroxamate of part C (500 mg, 0.82 mmol) in methanol (1 mL) and 1,4-dioxane (5 mL) was added 4 N hydrogen chloride/dioxane (2.5 mL). After stirring at ambient temperature for 1 hours, the solution was concentrated in vacuo. Trituration with diethyl ether provided the title compound as a white solid (490 mg, quantitative yield). HRMS MH+ calculated for C₂₃H₂₃N₄SO₅F₃: 525. Found: 525. MS MH⁺ calculated for C₂₃H₂₃F₃N₄O₅S: 525, found 525.

EXAMPLE 266 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide

[0900]

[0901] To a solution of the product of Preparative Example IX (2.08 g, 4.0 mmol) in warm water (200 mL) was added sodium bicarbonate to pH=8 and the solution was stirred for 1 hour. The resulting white solid was isolated by filtration, washed with water and dried at 40° C. for 48 hours to afford the title compound as a white solid (1.82 g, 94%). Analytical calculation for C₂₂H₂₃N₂SF₃O₅:H₂O, 52.50; H, 5.01; N, 5.57; S, 6.38. Found: C, 52.24; H, 4.65; N, 5.46; S, 6.75.

EXAMPLE 267 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methylbenzenesulfonate) (salt)

[0902]

[0903] To a solution of the product of Example 266 (550 mg, 1.10 mmol) in ethanol (5 mL) was added p-toluenesulfonic acid (240 mg, 1.26 mmol) and the reaction was then stirred for 3.5 hour. The resulting white solid was isolated by filtration, washed with ethanol and dried at 40° C. for 48 hours to afford the title compound as a white solid (633 mg, 86%). Recrystallized from methanol/water afforded the title compound as analytically pure material. Analytical Calculation for C₂₉H₃₁N₂S₂F₃O₉: 51.78; H, 4.64; N, 4.16. Found: C, 51.44; H, 4.32; N, 4.18.

EXAMPLE 268 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarbox-amide monomethanesulfonate (salt)

[0904]

[0905] To a solution of the product of Example 266 (550 mg, 1.13 mmol) in ethanol (5 mL) was added methane sulfonic acid (82 μL) and the reaction was then stirred for 3.5 hours. Concentration in vacuo afforded the title compound as a solid (640 mg, 97%). Recrystallization from methanol afforded analytically pure title compound. Analytical Calculation for C₂₃H₂₇N₂S₂F₃O₉: 46.30; H, 4.56; N, 4.70, S, 10.75. Found: C, 46.10; H, 4.71; N, 4.65; S, 10.99.

EXAMPLE 269 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide

[0906]

[0907] To a solution of the product of Preparative Example X (2.15 g, 4.0 mmol) in warm water (200 mL) was added sodium bicarbonate to pH=8. The solution was stirred for 1 hour. The resulting white solid was isolated by filtration, washed with water and dried at 40 degrees Celsius for 48 hours to afford the titled compound as a white solid (1.96 g, 98%). Analytical Calculation for C₂₂H₂₃N₂SF₃O₅:2H₂O: C, 51.26; H, 5.24; N, 5.44; S, 6.21. Found: C, 50.58; H, 4.72; N, 5.33; S, 6.04.

EXAMPLE 270 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methylbenzenesulfonate)(salt)

[0908]

[0909] To a solution of the product of Example 269 (550 mg, 1.13 mmol) in ethanol (5 mL) was added p-toluenesulfonic acid (248 mg, 1.26 mmol) and the solution was stirred for 3.5 hours. The resulting white solid was isolated by filtration, washed with ethanol and dried at 40° C. for 48 hours to afford the title compound as a white solid (705 mg, 95%). Recrystallized from methanol afforded analytically pure material. Analytical Calculation for C₂₉H₃₁N₂S₂F₃08: C, 53.04; H, 4.76; N, 4.27; S, 9.77 Found: C, 52.94; H, 4.46; N, 4.30; S, 9.99.

EXAMPLE 271 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarbox-amide monomethanesulfonate (salt)

[0910]

[0911] To a solution of the product of Example 269 (550 mg, 1.13 mmol) in ethanol (5 mL) was added methane sulfonic acid (79 μL) and the reaction was stirred for 3.5 hours. Concentration in vacuo gave the title compound as a solid (569 mg, 87%). Analytical Calculation for C₂₃H₂₇N₂S₂F₃08: C, 47.58; H, 4.69; N, 4.82. Found: C, 47.15; H, 4.18; N, 4.74.

EXAMPLE 272 Preparation of 1-acetyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide

[0912]

[0913] Part A: To a solution of the product of Preparative Example II, Part D (33.2 g, 80.0 mmol) in dimethylformamide (150 mL) was added cesium carbonate (65.2-g, 200 mmol) and 4-(trifluromethoxy)phenol (21.4 g, 120 mmol). The solution was mechanically stirred at sixty degrees Celsius for 24 hours. The solution was then diluted with water (1 L) and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on silica gel eluting with 20% ethyl acetate/hexane provided the desired diaryl sulfide as a white solid (45.0 g, quantitative yield).

[0914] Part B: To a solution of the diaryl sulfide from part A (24 g, 42.8 mmol) in ethanol (80 mL) and tetrahydrofuran (80 mL) was added a solution of NaOH (14.8 g, 370 mmol) in water (100 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH 5.0 and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid as a white foam (23.0 g, quantitative yield)

[0915] Part C: To a solution of carboxylic acid of part B (22.8 g, 43.0 mmol) in ethyl acetate (400 mL) cooled to zero degrees Celsius was bubbled gaseous Hydrogen chloride for 20 minutes. The reaction was stirred at this temperature for 2.5 hours. The solution was then concentrated in vacuo to afford the desired hydrochloride salt as a white foam (21.0 g, quantitative yield).

[0916] Part D: To a solution of the hydrochloride salt of part C (17.0 g, 35.0 mmol) in acetone (125 mL) and water (125 mL) was added triethyl amine (24 mL, 175 mmol). The reaction was cooled to zero degrees Celsius and acetyl chloride (3.73 mL, 53.0 mmol) was added. The solution was then stirred at ambient temperature for 18 hours. Concentration in vacuo gave a residue which was acidified with aqueous hydrochloric acid to pH 1.0 and then extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired methanesulfonamide as a white solid (17.0 g, quantitative yield).

[0917] Part E: To a solution of the methanesulfonamide of part D (14.4 g, 29.6 mmol) in dimethylformamide (250 mL) was added 1-hydroxybenzotriazole (4.8 g, 35.5 mmol), N-methyl morpholine (12.3 mL, 88.8 mmol) and O-tetrahydropyranyl hydroxylamine (5.2 g, 44.4 mmol) followed by 1-3-(dimethylamino) propyl]-3-ethyl carbodiimide hydrochloride (7.99 g, 41.4 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with water (500 mL) and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on a C₁₈ reverse phase column eluting with acetonitrile/water provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (12.0 g, 71%).

[0918] Part F: To a solution of tetrahydropyranyl-protected hydroxamate of part E (12.0 g, 20.5 mmol) in dioxane (250 mL) and methanol (50 mL) was added 4 N hydrogen chloride/dioxane (51 mL). After stirring at ambient temperature for 3.5 hours the solution was concentrated in vacuo. Trituration with diethyl ether and filtration provided the title compound as a white solid (8.84 g, 85%). HRMS MH⁺ calculated for C₂₁H₂₁N₂SO₇F₃: 503502.1021. Found 502.0979.

EXAMPLE 273 Preparation of N-hydroxy-1-(methyl sulfonyl)-4-[[4-[4-sulfonyl]-(trifluoromethoxy) phenoxy] phenyl]-4-piperidinecarboxamide

[0919]

[0920] Part A: To a solution of the product of Preparative Example II, Part D, (33.2 g, 80.0 mmol) in dimethylformamide (150 mL) was added cesium carbonate (65.2 gm, 200.0 mmol) and 4-(trifluromethoxy)phenol (21.4 g, 120 mmol). The solution was mechanically stirred at sixty degrees Celsius for 24 hours. The solution was then diluted with water (1 L) and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on silica gel eluting with 20% ethyl acetate/hexane provided the desired diaryl sulfide as a white solid (45.0 gm, quantitative yield).

[0921] Part B: To a solution of the diaryl sulfide from part A (21 g, 37.0 mmol) in ethanol (80 mL) and tetrahydrofuran (80 mL) was added a solution of NaOH (14.8 g, 370 mmol) in water (75 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=5.0, and then extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid as a white foam (19.3 g, 97%)

[0922] Part C: To a solution of carboxylic acid of part B (19.3 g, 37.0 mmol) in ethyl acetate (400 mL) cooled to zero degrees Celsius was bubbled gaseous hydrogen chloride for 30 minutes. The reaction was stirred at this temperature for 2.5 hours. The solution was then concentrated in vacuo to afford the desired hydrochloride salt as a white foam (15.8 g, 93%).

[0923] Part D: To a solution of the hydrochloride salt of part C (15.8 g, 33.0 mmol) in acetone (100 mL) and water (100 mL) was added triethyl amine (23 mL, 164 mmol). The reaction was cooled to zero degrees Celsius and methanesulfonyl chloride (5.1 mL, 66.0 mmol) was added. The solution was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo and acidified with aqueous hydrochloric acid to pH 1.0. The aqueous residue was extracted ethyl acetate. The organic extract was washed with water, saturated sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid methanesulfonamide as a white solid (17.6 gm, quantitative yield).

[0924] Part E: To a solution of the methanesulfonamide of part D (18 g, 35.0 mmol) in dimethylformamide (150 mL) was added 1-hydroxybenzotriazole (5.66 gm, 42.0 mmol), N-methyl morpholine (14.0 mL, 105.0 mmol) and O-tetrahydropyranyl hydroxylamine (6.1 g, 52 mmol) followed by 1-3-(dimethylamino) propyl]-3-ethyl carbodiimide hydrochloride (9.4 gm, 49.0 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with water (500 mL) and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on a C₁₈ reverse phase column eluting with acetonitrile/water provided desired tetrahydropyranyl-protected hydroxamate as a white solid (8.17 g, 41%).

[0925] Part F: To a solution of tetrahydropyranyl-protected hydroxamate of part E (8.17 g, 13.0 mmol) in dioxane (100 mL) and methanol (100 mL) was added 4 N hydrogen chloride/dioxane (50 mL). After stirring at ambient temperature for 3.5 hours the solution was concentrated in vacuo. Trituration with diethyl ether provided the title compound as a white solid (6.83 g, 92%). MS MH⁺ calculated for C₂₀H₂₁NS₂O₈F: 539. Found 539.

[0926] The following compounds were prepared by parallel synthesis (resin based synthesis, automated synthesis) procedures utilizing reactions such as acylation and nucleophilic displacement:

EXAMPLE 274

[0927]

EXAMPLE 275

[0928]

EXAMPLE 276

[0929]

EXAMPLES: 277-315

[0930]

MS (ES) Example R₁R₂NH Amine m/z 277

Ethyl amine 592 (M + H) 278

3-(Aminomethyl) pyridine 655 (M + H) 279

Imidazole 615 (M + H) 280

3-Amino-1-propanol 622 (M + H) 281

Histamine 658 (M + H) 282

2-Thiophene methyl amine 660 (M + H) 283

Morpholine 634 (M + H) 284

2-(Aminomethyl) pyridine 655 (M + H) 285

4-(Aminomethyl) pyridine 655 (M + H) 286

Ethanolamine 608 (M + H) 287

N,N,N-Trimethyl ethylenediamine 649 (M + H) 288

1-Methylpiperazine 647 (M + H) 289

N,N-Dimethyl ethylenediamine 635 (M + H) 290

Piperazine 633 (M + H) 291

Thiomorpholine 650 (M + H) 292

N-Propylcyclopropne methylamine 660 (M + H) 293

(Aminomethyl) cyclopropane 618 (M + H) 294

Dimethylamine 592 (M + H) 295

Diethylamine 620 (M + H) 296

Piperidine 632 (M + H) 297

(R)-(−)-2- Pyrrolidine methanol 648 (M + H) 298

Pyrrolidine 618 (M + H) 299

1-(2-(2- Hydroxyethoxy) ethyl)piperazine 721 (M + H) 300

Isonipecotamide 675 (M + H) 301

2-(2-Aminoethoxy) ethanol 652 (M + H) 302

3,3′-Iminobis(N,N- dimethylpropylamine) 734 (M + H) 303

Bis(2-Methoxy ethyl)amine 680 (M + H) 304

4-Hydroxy piperidine 648 (M + H) 305

N-(Carboethoxy methylpiperazine 719 (M + H) 306

1-(2-Morpholinoethyl) piperazine 746 (M + H) 307

1-(2-Methoxyethyl) piperazine 691 (M + H) 308

1-(2- Dimethylaminoethyl) piperazine 704 (M + H) 309

2-Methoxyethylamine 622 (M + H) 310

2,2,2-Trifluoroethyl amine 646 (M + H) 311

1,2,4-Triazole 616 (M + H) 312

Methoxyamine 594 (M + H) 313

Ethyl isonipecotate 704 (M + H) 314

2-Pyrrolidinone 632 (M + H) 315

Isonipecotic acid 676 (M + H)

EXAMPLES: 316-332

[0931] Example R₁R₂NH Amine MS (ES) m/z 316

3-(Aminomethyl) pyridine 593 (M + H) 317

Imidazole 553 (M + H) 318

Piperidine 570 (M + H) 319

Morpholine 572 (M + H) 320

2-(Aminomethyl) pyridine 593 (M + H) 321

Ethanolamine 546 (M + H) 322

2,2,2-Trifluoro ethylamine 584 (M + H) 323

N,N,N-Trimethyl ethylenediamine 587 (M + H) 324

1-Methylpiperazine 585 (M + H) 325

4-(Aminomethyl) pyridine 593 (M + H) 326

Pyrrolidine 556 (M + H) 327

Bis(2-Methoxy ethyl)amine 618 (M + H) 328

Piperazine 571 (M + H) 329

4-(Ethylamino methyl)pyridine 621 (M + H) 330

1-(2-Methoxy ethyl)pyridine 629 (M + H) 331

N- Propylcyclopropane methylamine 598 (M + H) 332

2-Methoxyethylamine 560 (M + H)

EXAMPLES: 333-347

[0932] Example R₁R₂NH Amine MS (ES) m/z 333

3-(Aminomethyl) pyridine 635 (M + H) 334

Piperidine 612 (M + H) 335

Morpholine 614 (M + H) 336

2-(Aminomethyl) pyridine 635 (M + H) 337

Ethanolamine 588 (M + H) 338

N,N,N-Trimethyl ethylenediamine 629 (M + H) 339

1-Methylpiperazine 627 (M + H) 340

4-(Aminomethyl) pyridine 636 (M + H) 341

Pyrrolidine 598 (M + H) 342

Bis(2-Methoxy ethyl)amine 660 (M + H) 343

Piperazine 613 (M + H) 344

4-(Ethylamino methyl)pyridine 663 (M + H) 345

1-(2-Methoxy ethyl)pyridine 671 (M + H) 346

N-Propylcyclopropane methylamine 640 (M + H) 347

2-Methoxyethylamine 602 (M + H)

EXAMPLES 348-942

[0933] The following compounds were prepared in a manner similar to that used in the preceding examples. In the tables that follow, a generic structure is shown above the table with substituent groups being illustrated in the table along with available mass spectral data.

Example R K MS (ES) m/z 348

349

499.1131 350

583 351

580.1366 352

538.1282 353

610 354

355

648 356

357

610 358

359

648 360

361

616 362

614 363

616 364

648 365

614 366

648 367

368

369

370

371

372

539.1201 373

374

567.1120 375

590.1174 376

378

474.1567 379

555 380

537.1412 381

523 382

383

384

547.1279 385

386

555.1516 387

607.1061 388

389

516 390

539 391

538.1272 392

538.1252 393

394

395

522.1351 396

582.2245 397

532.2280 398

399

528 400

401

515.3344 402

582.2266 403

404

550 405

550 406

555 407

408

600.2162 409

548 410

411

412

502 413

529 414

600.2141 415

600 416

489 417

530 418

598.2200 419

548.2013 420

569.2259 421

570.2186 422

635.2185 423

636.2104 424

586.2059 425

562.1957 426

585.1968 427

586.1936 428

637.2137 429

638.2072 430

637.2146 431

638.2075 432

602.1731 433

654.1921 434

654.1932 435

636 436

596 437

—H 502 438

579 439

411.1211 440

480 441

542 442

540 443

—H 440 444

518 445

566 446

618 447

616 448

550.2387 449

616 450

451

580.1370 452

453

454

614 455

456 456

585 457

463 458

549 459

532 460

—H 574 461

564 462

616 463

598 464

514

[0934]

Example R MS (ES) m/z 465

505.1746 466

551 (+Na) 467

468

463.1704 469

486 470

503 471

537 472

533.2348 473

499.2304 474

504 475

476

532.2522 477

478

479

539.0842 480

545.1595 481

574.1483 482

503.2238 483

515.2234 484

417 485

475.1910 486

383 487

460 488

438 489

452 490

474 491

476 492

383 493

472 494

472 495

383 496

383 497

517 498

499

503 500

521 501

571 502

571 503

571 504

489.2059 505

507.1987 506

557 507

557 508

557 509

503.2226 510

521.2122 511

571.2056 512

571.2054 513

571.1464 514

379.0964 515

504.1831 516

532.2105 517

470.1935 518

576.2355 519

596.2033 520

518.1945 521

538.1372 522

519 523

560 524

399 525

413 526

493 527

581 528

343.1742 529

399.1597 530

483 531

501 532

551 533

407 534

515 535

460 536

460 537

464 538

460 539

412 540

495.4984 541

479.1416 542

572.2800 543

539.2017 544

489.2049 545

497 546

506 547

479 548

524 549

542 550

520 551

520 552

506 553

476 554

547.2525 555

561.2692 556

561.2679 557

576.2184 558

511.1755 559

500.1830 560

500.1888 561

577.1650 562

413.1750 563

427.1903 564

385.1457 565

637.2067 566

532.2448 567

529.1631 568

529.1603 569

574.1478 570

597.0849 571

574.1473 572

513.1228 573

509.1536 574

509.1529 575

493.1803 576

493.1838 577

476.1847 578

476.1865 579

553.1057 580

476.1879 581

489.2076 582

507.2016 583

584

585

415.1559 586

401.1399 587

443 588

477 589

515 590

538 591

452 592

466 593

472 594

502 595

556 596

457 597

598

415.1911 599

471 600

575.2777 601

575 602

589.2947 603

589.2914 604

601.2936 605

587.2808 606

551.2225 607

587.2048 608

619.2098 609

687.1978 610

857.2070 611

719.2024 612

401.1746 613

581.2323 614

511.1900 615

495.1368 616

521.1980 617

529.0962 618

505.2031 619

475.1898 620

529.1604 621

456.1761 622

398.1751 623

414.1690 624

434.1651 629

510 634

483.1992 635

425 636

507.1910 637

489.2064 638

511.1910 639

521.1962 640

505.2006 641

513.1277 642

517.2410 643

519.2190 644

505 645

428.1821 646

428 647

503 648

506.1830 649

524 650

524.1531 651

490.1912 652

487 653

487 654

491 655

503 656

473 658

659

665

510.1353 666

541.1815 667

475 668

510.1366 669

510.1358 670

671

524 672

535 673

594 674

524 675

578 676

578 677

578 678

540 679

594 680

555 681

528 682

528 683

570 684

514 685

516 686

384.1593 688

527.1658 (M + NH4) 690

535 691

568 692

423.1946 693

441.2080 694

506.1857 695

530.1565 696

540 697

592.1401 698

554.1659 699

608.1355 706

490.1929 707

491 708

714

560.1568 720

459.1987 721

508.2019 722

480.1700 723

441.2053 724

509 725

557 726

557 727

541 728

491 729

541 730

501 731

509 732

501 733

501 734

517 735

521 736

505 737

501 738

559 740

741

752

572 755

467 756

453 757

453 758

451 759

451 760

488 761

451 781

444 782

444 784

786

499 787

499 788

515 789

529 790

516 791

517 793

794

796

517 797

798

799

802

807

811

815

816

822

823

825

826

827

828

829

830

831

832

833

834

835

836

838

841

842

844

845

846

847

848

850

851

852

853

854

856

857

858

859

860

861

862

863

864

867

868

869

872

873

877

878

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

899

901

902

905

906

909

910

911

912

913

914

915

916

920

921

922

924

926

931

932

939

[0935]

Example R K MS 940

941

942

Example 943 In Vitro Metalloprotease Inhibition

[0936] The compounds prepared in the manner described in the Examples above were assayed for activity by an in vitro assay. Following the procedures of Knight et al., FEBS Lett. 296(3):263 (1992). Briefly, 4-aminophenylmercuric acetate (APMA) or trypsin-activated MMPs were incubated with various concentrations of the inhibitor compound at room temperature for 5 minutes.

[0937] More specifically, recombinant human

[0938] MMP-13, MMP-1, MMP-2 and MMP-9 enzymes were prepared in laboratories of the assignee following usual laboratory procedures. MMP-13 from a full length cDNA clone was expressed as a proenzyme using a baculovirus as discussed in V. A. Luckow, Insect Cell Expression Technology, pages 183-218, in Protein Engineering: Principles and Practice, J. L. Cleland et al eds., Wiley-Liss, Inc., (1996). See, also, Luckow et al., J. Virol., 67:4566-4579 (1993); .O'Reilly et al., Baculovirus Expression Vectors: A Laboratory Manual, W. H. Freeman and Company, New York, (1992); and King et al., The Baculovirus Expression System: A Laboratory Guide, Chapman & Hall, London (1992) for further details on use of baculovirus expression systems. The expressed enzyme was purified first over a heparin agarose column and then over a chelating zinc chloride column. The proenzyme was activated by APMA for use in the assay.

[0939] MMP-1 expressed in transfected HT-1080 cells was provided by Dr. Harold Welgus of Washington University, St. Louis, Mo. The enzyme was also activated using APMA and was then purified over a hydroxamic acid column. Dr. Welgus also provided transfected HT-1080 cells that expressed MMP-9. Transfected cells that expressed MMP-2 were provided by Dr. Gregory Goldberg, also of Washington University. Studies carried out using MMP-2 in the presence of 0.02% 2-mercaptoethanol are shown in the table below with an asterisk. Studies with MMP-7 were carried out at pH 7.5 in the presence of 0.02% 2-mercaptoethanol using conditions otherwise similar to those used for the other enzymes. The enzyme was obtaind from a hMMP-7-expressing E. coli clone that was a gift of Dr. Steven Shapiro of Washington University, St. Louis, Mo. Further specifics for preparation and use of these enzymes can be found in the scientific literature describing these enzymes. See, for example, Enzyme Nomenclature, Academic Press, San Diego, Calif. (1992) and the citations therein, and Frije et al., J. Biol. Chem., 26(24): 16766-16773 (1994). The enzyme substrate is a methoxycoumarin-containing polypeptide having the following sequence:

[0940] MCA-ProLeuGlyLeuDpaAlaArgNH₂, wherein MCA is methoxycoumarin and Dpa is 3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate is commercially available from Baychem as product M-1895.

[0941] The buffer used for assays contained 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl₂ and 0.05 percent polyethyleneglycol (23) lauryl ether at a pH value of 7.5. Assays were carried out at room temperature, and dimethyl sulfoxide (DMSO) at a final concentration of 1 percent was used to dissolve inhibitor compound.

[0942] The assayed inhibitor compound in

[0943] DMSO/buffer solution was compared to an equal amount of DMSO/buffer with no inhibitor as control using Microfluor White Plates (Dynatech). The inhibitor or control solution was maintained in the plate for 10 minutes and the substrate was added to provide a final concentration of 4 μM.

[0944] In the absence of inhibitor activity, a fluorogenic peptide was cleaved at the gly-leu peptide bond, separating the highly fluorogenic peptide from a 2,4-dinitrophenyl quencher, resulting in an increase of fluorescence intensity (excitation at 328 nm/emission at 415 nm). Inhibition was measured as a reduction in fluorescent intensity as a function of inhibitor concentration, using a Perkin Elmer L550 plate reader. The IC₅₀ values were calculated from those values. The results are set forth in the Inhibition Table A, below, reported in terms of IC₅₀ to three significant figures, where appropriate. Inhibition Table A (nM) Example MMP-13 MMP-2 MMP-1 Number IC₅₀(nM) IC₅₀(nM) IC₅₀(nM) 1 22.7 8.5 >10,000 2 5,500 6,000 >10,000 8 15.6 2,900 >10,000 9 15.6 2,900 >10,000 10 18.1 >10,000 >10,000 11 18.0 4,500 >10,000 12 50.0 2,500 >10,000 13 12.2 5,600 >10,000 14 40.0 6,000 >10,000 15 37.0 2,700 >10,000 16 6.70 1,400 >10,000 17 31.6 3,500 >10,000 18 45.0 >10,000 >10,000 19 28.0 5,500 >10,000 20 42.5 4,800 >10,000 21 70.0 7,000 >10,000 22 >10,000 >10,000 >10,000 23 90.0 10,000 >10,000 24 23.5 4,500 >10,000 25 6.00 1,600 >10,000 26 10.7 3,600 >10,000 27 6.40 1,600 >10,000 28 6.70 700 >10,000 29 4.00 445 >10,000 32 10.0 800 >10,000 33 20.0 4,500 >10,000 34 18.1 >10,000 >10,000 35 30.0 9,000 >10,000 36 15.8 2,100 >10,000 37 30.0 1,750 >10,000 38 67.4 6,000 67.4 39 19.3 3,700 >10,000 40 26.8 900 >10,000 41 70.0 5,400 >10,000 42 82.5 >10,000 >10,000 43 17.9 5,000 >10,000 44 19.0 1,050 >10,000 45 360 5,000 >10,000 46 80.0 5,700 >10,000 47 11.4 6,000 >10,000 48 27.0 3,200 >10,000 49 20.0 6,500 >10,000 51 370 7,000 >10,000 52 90.0 1,900 >10,000 53 28.9 1,400 >10,000 54 40.0 5,700 >10,000 55 10.0 >10,000 >10,000 56 55.0 3,500 >10,000 57 80.0 2,700 >10,000 58 22.0 4,000 >10,000 59 4.00 530 >10,000 60 13.9 3,700 >10,000 61 7.00 1,500 >10,000 62 14.0 690 >10,000 63 20.0 2,900 >10,000 64 19.3 770 >10,000 65 5.00 195 >10,000 66 8.00 240 >10,000 68 13.0 1,800 >10,000 69 18.1 3,500 >10,000 70 10.6 700 >10,000 71 7.70 270 >10,000 72 13.0 800 >10,000 73 15.4 2,000 >10,000 74 9.00 80.0 >10,000 75 11.5 500 >10,000 76 9.00 250 >10,000 77 75.0 3,400 >10,000 78 11.7 730 >10,000 79 20.0 2,000 >10,000 80 4.10 562 >10,000 81 60.0 158 >10,000 82 6.70 490 >10,000 83 2.70 21.1 3,100 84 28.6 1,400 >10,000 85 130 370 >10,000 86 0.6 12.1 >10,000 87 4.00 15.5 >10,000 88 9.00 40.0 >10,000 91 0.3 <0.1 >10,000 92 0.8 0.1 >10,000 95 0.3 <0.1 3,600 96 0.4 0.1 7,300 97 0.6 <0.1 >10,000 98 1.70 0.2 >10,000 99 1.00 <0.1 >10,000 100 0.5 <0.1 6,000 101 1.10 0.8 >10,000 102 0.6 0.2 >10,000 103 1.80 0.3 >10,000 104 0.25 0.2 10,000 105 1.10 0.3 10,000 106 0.2 0.15 >10,000 106 0.1 <0.1 8,200 108 0.2 <0.1 5,000 109 0.3 <0.1 >10,000 110 0.6 0.2 >10,000 111 0.8 0.15 >10,000 112 0.5 <0.1 >10,000 113 0.3 <0.1 >10,000 114 0.4 <0.1 >10,000 115 0.1 <0.1 >10,000 116 0.3 <0.1 >10,000 117 0.2 0.1 >10,000 118 0.2 <0.1 >10,000 119 0.3 0.3 >10,000 120 0.4 0.1 >10,000 121 0.2 0.1 5,000 122 0.2 <0.1 3,000 123 0.7 <0.1 >10,000 124 <0.1 <0.1 >10,000 125 0.4 <0.1 >10,000 126 0.7 <0.1 >10,000 127 2.90 0.2 >10,000 128 0.1 <0.1 3,400 129 37.2 3.00 >10,000 130 0.5 0.3 1,600 131 0.2 <0.1 8,000 132 0.5 <0.1 >10,000 133 1.40 0.3 >10,000 134 1.80 0.3 >10,000 135 0.6 0.3 10,000 136 0.9 <0.1 >10,000 137 0.8 0.1 10,000 138 3.90 0.25 >10,000 140 11.4 0.8 >10,000 141 20.0 9.00 >10,000 142 12.6 10.0 >10,000 143 22.0 14.5 >10,000 144 0.4 0.2 10,000 145 0.4 0.2 3,700 146 0.2 0.3 3,000 147 0.4 0.2 7,700 148 2.50 3.70 >10,000 149 15.8 13.8 480 150 175 175 >10,000 151 270 290 >10,000 152 2.00 59.0 >10,000 153 50.0 5,000 >10,000 154 18.0 3,700 >10,000 155 130 240 >10,000 156 2.20 0.45 >10,000 157 0.5 0.2 >10,000 160 300 90.0 >10,000 161 32.6 900 >10,000 162 27.8 7,000 >10,000 163 44.5 2,500 >10,000 164 3.50 440 >10,000 165 3.00 48.5 >10,000 166 32.7 240 >10,000 168 50.0 285 >10,000 169 20.0 175 >10,000 170 2.40 200 >10,000 171 5.40 186 >10,000 172 3.80 160 >10,000 173 6.70 330 3,400 174 23.5 800 >10,000 175 2.50 290 >10,000 176 4.00 250 >10,000 177 8.80 520 10,000 178 18.1 325 >10,000 179 20.6 170 >10,000 180 1.10 41.8 >10,000 181 190 2,300 >10,000 183 300 1,500 >10,000 184 480 1,500 >10,000 185 2.20 32.6 >10,000 187 10.0 600 >10,000 188 7.0 235 >10,000 189 7.00 235 >10,000 190 4.70 136 >10,000 191 3.50 25.1 >10,000 193 3.50 0.15 >10,000 194 0.3 <0.1 >7,300 195 1.00 0.2 >10,000 196 1.60 <0.1 >10,000 197 2.70 <0.1 >10,000 198 0.375 0.25 7,300 199 0.2 <0.1 3,000 200 0.2 <0.1 3,000 201 0.3 0.2 >10,000 202 0.4 0.2 >10,000 207 28.8 900 >10,000 208 110 1,000 >10,000 209 50.0 130 >10,000 210 5.40 4.50 4,000 211 11.4 1,200 >10,000 212 160 240 >10,000 213 1,400 2,700 >10,000 214 4,900 3,500 >10,000 224 <0.1 <0.1 4,500 225 180 41.8 >10,000 227 28.8 21.7 >10,000 228 2,448 2,000 >10,000 229 0.18 0.1 >10,000 231 0.2 0.1 >10,000 233 43.5 2,050 >10,000 235 235 5,300 >10,000 236 9.00 400 >10,000 237 13.0 1,900 >10,000 238 80.0 10,000 >10,000 239 9.00 8,300 >10,000 240 76.9 10,000 >10,000 241 4.80 >10,000 >10,000 242 42.5 1,500 >10,000 243 11.3 420 >10,000 244 67.4 4,400 >10,000 245 20.0 800 >10,000 246 32.7 2,700 >10,000 247 34.5 1,600 >10,000 248 2.29 270 >10,000 249 13.0 235 >10,000 251 <0.1 <0.1 5,840 252 <0.1 <0.1 3,933.33 253 <0.1, 3,400 <0.1 0.15 256 0.2 0.1 3,200 257 0.2 0.1 4,100 258 0.2 0.1 >10,000 260 0.1 <0.1 5,300 261 <0.1 <0.1 3,700 262 1.50 0.9 >10,000 264 0.2 <0.1 4,500 265 0.2 1.30, >10,000 <0.1 266 0.1 <0.1 5,500 267 0.2 0.15 10,000 268 <0.1, 4,000 <0.1 0.2 269 0.2 <0.1 >10,000 270 1.00 1.00 >10,000 271 0.3 0.17 >10,000 272 0.2 0.1 3,600 273 0.3 0.1 >10,000 274 160 >10,000 >10,000 275 70.0 >10,000 >10,000 276 37.3 >10,000 >10,000 277 70.0 >10,000 >10,000 278 19.3 >10,000 >10,000 279 20.0 7,300 >10,000 280 90.0 >10,000 >10,000 281 105 >10,000 >10,000 282 14.8 9,000 >10,000 283 13.8 >10,000 >10,000 284 130 >10,000 >10,000 285 19.3 9,000 >10,000 286 60.0 >10,000 >10,000 287 150 >10,000 >10,000 288 35.0 >10,000 >10,000 289 50.0 >10,000 >10,000 290 50.0 >10,000 >10,000 292 100 >10,000 >10,000 293 63.1 >10,000 >10,000 294 59.1 >10,000 >1,000 295 50.0 >10,000 >10,000 296 50.0 >10,000 >10,000 297 34.9 >10,000 >10,000 298 40.0 >10,000 >10,000 299 30.6 9,000 >10,000 300 37.3 >10,000 >10,000 301 90.0 >10,000 >10,000 302 175 >10,000 >10,000 303 115 >10,000 >10,000 304 30.6 7,000 >10,000 305 28.6 >10,000 >10,000 306 60.0 >10,000 >10,000 307 40.0 >10,000 >10,000 308 40.0 10,000 >10,000 309 48.5 >10,000 >10,000 310 60.0 10,000 >10,000 311 120 >10,000 >10,000 312 200 >10,000 >10,000 313 77.0 >10,000 >10,000 314 65.0 >10,000 >10,000 315 420 >10,000 >10,000 316 0.4 0.2 >10,000 317 1.40 0.4 >10,000 318 0.3 0.1 >10,000 319 0.5 0.2 >10,000 320 12.1 4.00 >10,000 321 0.5 0.3 >10,000 322 0.3 0.3 >10,000 323 1.30 0.4 >10,000 324 0.7 0.4 >10,000 325 0.9 0.2 >10,000 326 0.6 0.45 >10,000 327 0.9 0.3 >10,000 328 0.35 0.4 >10,000 329 0.9 0.4 >10,000 330 0.5 0.7 >10,000 331 0.7 0.2 >10,000 332 2.10 0.4 >10,000 333 0.8 0.2 >10,000 334 0.7 0.3 >10,000 335 0.9 0.15 >10,000 336 1.00 <0.1 >10,000 337 2.70 0.2 >10,000 338 1.90 0.2 >10,000 339 1.00 0.3 >10,000 340 0.3 <0.1 >10,000 341 0.6 0.2 >10,000 342 4.00 0.3 >10,000 343 1.70 0.8 >10,000 344 2.90 0.65 >10,000 346 1.20 0.2 >10,000 347 3.00 0.7 >10,000 348 16.5 0.8 >10,000 349 0.2 <0.1 2600 350 0.1 <0.1 6000 351 — — — 352 1.4 0.3 >10,000 353 0.3 <0.1 >10,000 354 1.6 15.4 355 0.4 <0.1 7000 356 2.4 32.6 357 0.3 0.1 >10,000 358 — — — 359 34.9 12.2 >10,000 360 10.0 5.6 361 0.5 <0.1 5000 362 2.7 <0.1 >10,000 363 0.4 0.2 8800 364 1.0 0.2 >10,000 365 0.3 0.1 >10,000 366 13.0 2.5 >10,000 367 — — — 368 0.5 7.0 369 3.3 5.4 370 371 11.1 400 372 — — — 373 3.0 80.0 374 3.3 4.0 >10,000 375 16.9 15.6 >10,000 376 5.5 230 378 1.7 0.3 200 379 0.3 0.1 >10,000 380 — — — 381 — — — 382 11.4 260 383 3.0 700 >10,000 384 — — — 385 — — — 386 0.4 0.2 2100 387 — — — 388 50.0 430 389 1.7 16.1 >10,000 390 — — — 391 0.1 <0.1 5400 392 0.2 0.1 >10,000 393 4.5 427 >10,000 394 0.5 8.0 395 0.9 0.5 >10,000 396 4.8 330 >10,000 397 4.4 70.0 >10,000 398 7.0 70.0 >10,000 399 1.2 0.3 >10,000 400 23.5 520 401 16.9 195 >10,000 402 15.8 340 >10,000 403 55.3 4.0 >10,000 404 0.5 0.25 >10,000 405 406 407 1.2 0.1 >10,000 408 25.1 800 >10,000 409 22.4 275 >10,000 410 0.6 0.25 >10,000 411 0.2 <0.1 >10,000 412 0.4 0.2 6400 413 1.1 0.3 8000 414 50.5 1500 >10,000 415 50.4 246 >10,000 416 0.4 0.2 3000 417 0.7 4.5 >10,000 418 7.0 1400 >10,000 419 4.2 400 >10,000 420 — — — 421 — — — 422 — — — 423 — — — 424 5.5 80.0 >10,000 425 20.0 1000 >10,000 426 — — — 427 — — — 428 — — — 429 — — — 430 — — — 431 — — — 432 13.9 100 >10,000 433 450 3500 >10,000 434 190 3700 >10,000 435 5.9 1500 >10,000 436 1.8 330 >10,000 437 18.1 800 >10,000 438 1.4 160 >10,000 439 1070 1600 >10,000 440 26.8 240 >10,000 441 6.0 420 >10,000 442 10.0 211 >10,000 443 90.0 2200 >10,000 444 — — — 445 90.0 1200 >10,000 446 270 7000 >10,000 447 23.9 155 >10,000 448 2.4 540 >10,000 449 — — — 450 — — — 451 0.3 0.1 3700 452 <0.1 <0.1 453 0.4 35.0 >10,000 454 2.1 100 >10,000 455 6.3 26.8 >10,000 456 — — — 457 1800 2700 >10,000 458 210 2100 >10,000 459 136 3100 >10,000 460 4.0 200 >10,000 461 20.0 145 >10,000 462 2.9 80.0 >10,000 463 16.9 210 >10,000 464 120 400 >10,000 465 80 370 >10,000 466 9.4 60 >10,000 467 27.0 140 >10,000 468 — — — 469 0.8 12.0 >10,000 470 140 2000 >10,000 471 2400 >10,000 >10,000 472 4.0 200 >10,000 473 160 3300 >10,000 474 12.1 300 >10,000 475 27.1 500 >10,000 476 25.4 140 >10,000 477 11.3 160 >10,000 478 16.4 306 >10,000 479 5.0 60.0 >10,000 480 18.6 155 >10,000 481 50.0 1400 >10,000 482 6.0 4.0 >10,000 483 32.6 10.6 >10,000 484 240 100 >10,000 485 8.0 4.2 >10,000 486 5400 4000 >10,000 487 140 800 >10,000 488 140 370 >10,000 489 770 1900 >10,000 490 61.0 3000 >10,000 491 >10,000 >10,000 >10,000 492 6100 >10,000 >10,000 493 >10,000 >10,000 >10,000 494 650 3300 >10,000 495 14.5 21.1 >10,000 496 30.7 200 >10,000 497 50.0 8000 >10,000 499 0.9 19.3 >10,000 500 3.0 22.0 >10,000 501 2.5 180 >10,000 502 14.0 63 >10,000 503 10.0 50.0 >10,000 504 6.3 220 >10,000 505 14.0 72.0 >10,000 506 5.0 400 >10,000 507 15.8 210 >10,000 508 19.3 210 >10,000 509 520 >10,000 >10,000 510 7700 >10,000 >10,000 511 9000 6000 >10,000 512 7700 >10,000 >10,000 513 7700 >10,000 >10,000 514 1.0 0.6 5,000 515 8.0 27.0 >10,000 516 14.8 300 >10,000 517 14.0 1100 >10,000 518 11.4 350 >10,000 519 45.4 1300 >10,000 520 22.5 250 >10,000 521 3.5 50.0 >10,000 522 2.4 94.0 >10,000 523 2.4 190 >10,000 524 2700 6400 >10,000 525 290 700 >10,000 526 >10,000 >10,000 >10,000 527 6700 9000 >10,000 528 7700 >10,000 >10,000 529 8800 >10,000 >10,000 530 20.0 60.7 >10,000 531 13.0 10.0 >10,000 532 10.0 150 >10,000 533 60.0 150 >10,000 534 30.0 480 >10,000 535 1.9 35.0 >10,000 536 7.7 88.0 >10,000 537 70.0 55.0 5200 538 80.0 370 >10,000 539 270 350 >10,000 540 11.4 500 >10,000 541 0.7 2.0 >10,000 542 — — — 543 33.7 5400 >10,000 544 35.0 3100 >10,000 545 7.7 120 >10,000 546 2.7 18.6 >10,000 547 5.0 64.7 >10,000 548 40.0 800 >10,000 549 55.3 2900 >10,000 550 20.0 2000 >10,000 551 9.0 140 >10,000 552 12.8 140 >10,000 553 12.8 50.0 >10,000 554 3.7 140 >10,000 555 3.7 220 >10,000 556 4.5 170 >10,000 557 16.9 200 >10,000 558 4.5 66.4 >10,000 559 7.2 80.0 >10,000 560 4.5 306 >10,000 561 6.0 500 >10,000 562 1200 6300 >10,000 563 70.0 235 >10,000 564 150 550 >10,000 565 5.5 700 >10,000 566 15.8 57.1 >10,000 567 5.0 87.7 >10,000 568 120 4600 >10,000 569 16.9 87.7 >10,000 570 290 >10,000 >10,000 571 28.6 140 >10,000 572 37.2 3000 >10,000 573 11.4 235 >10,000 574 10.6 220 >10,000 575 10.7 110 >10,000 576 8.8 78.0 >10,000 577 107 2200 >10,000 578 160 2000 >10,000 579 2.7 100 >10,000 580 37.2 700 >10,000 581 27.0 480 >10,000 582 30.0 1800 >10,000 583 70.0 4700 >10,000 584 2700 3500 >10,000 585 1400 3500 >10,000 586 >10,000 >10,000 >10,000 587 1.8 1.0 >10,000 588 — — — 589 70.0 >10,000 >10,000 590 121 80.0 >10,000 591 70.0 730 >10,000 592 57.0 690 >10,000 593 420 650 >10,000 594 570 650 >10,000 595 270 425 >10,000 596 1.1 10.6 >10,000 597 670 700 >10,000 598 25.4 145 >10,000 600 9.0 600 >10,000 601 9.0 1300 >10,000 602 70.0 3000 >10,000 603 15.8 2300 >10,000 604 20.0 2500 >10,000 605 10.6 2000 >10,000 606 3.0 77.0 >10,000 607 2.9 220 >10,000 608 3.0 250 >10,000 609 30.6 2800 >10,000 610 425 1300 >10,000 611 139 1800 >10,000 612 290 2200 >10,000 613 8.0 30.7 >10,000 614 22.0 25.4 >10,000 615 3.1 11.0 >10,000 616 4.0 3.7 >10,000 617 7.0 5.7 >10,000 618 — — — 619 4.3 5.7 >10,000 620 27.8 225 >10,000 621 120 1500 >10,000 622 500 1600 >10,000 623 350 1400 >10,000 624 120 940 >10,000 634 4.4 60.7 >10,000 635 13.9 260 >10,000 636 3.0 8.0 >10,000 637 3.8 22 >10,000 638 — — — 639 1.5 1.5 9400 640 4.2 15.8 >10,000 641 4.0 13.7 >10,000 642 2.2 1.1 >10,000 643 1.8 1.2 6000 644 1.6 3.3 8800 645 370 1200 >10,000 646 — 7800 >10,000 647 6.0 160 >10,000 648 25.8 110 >10,000 649 130 1400 >10,000 650 14.7 1200 >10,000 651 13.7 60 >10,000 652 0.4 82.0 >10,000 653 0.8 160 >10,000 654 3.2 35.0 >10,000 655 37.3 1400 >10,000 656 3.1 120 >10,000 658 12.2 1000 >10,000 659 1.0 3.7 >10,000 665 2.3 29.2 >10,000 666 48.4 330 >10,000 667 30 135 >10,000 668 2.0 25.8 >10,000 669 4.3 22.7 >10,000 670 671 6.0 130 >10,000 672 6.7 60 >10,000 673 14.8 455 >10,000 674 8.0 110 >10,000 675 13.0 88 6000 676 7.7 90 >10,000 677 7.0 34.7 >10,000 678 5.0 50 >10,000 679 680 681 682 683 11.3 290 >10,000 684 60 1450 >10,000 685 3/0 34.7 >10,000 686 4200 3700 >10,000 688 17.6 110 >10,000 690 7.3 41.8 >10,000 691 10.0 130 >10,000 692 10.0 22.7 >10,000 693 210 1900 >10,000 694 3.1 23.2 >10,000 695 2.0 22.7 >10,000 696 10.0 140 >10,000 697 18.1 1500 >10,000 698 16.9 700 >10,000 699 50.0 455 >10,000 705 44.5 1100 >10,000 706 4.3 40 >10,000 707 2.3 9.0 >10,000 708 114 3000 >10,000 714 28.8 420 >10,000 720 4.5 36.9 >10,000 724 28.6 300 >10,000 725 25.1 210 >10,000 726 15.8 250 >10,000 727 34.9 240 >10,000 728 9.4 106 >10,000 729 14.8 240 >10,000 730 37 3000 >10,000 731 1.9 35 >10,000 732 3.1 590 >10,000 733 1.6 270 >10,000 734 6.0 3300 >10,000 735 9.0 800 >10,000 736 0.9 145 >10,000 737 3.0 1280 >10,000 738 22.0 270 >10,000 740 61 175 >10,000 741 50 125 >10,000 752 14.8 271 >10,000 755 2.2 20 >10,000 756 7.0 28.8 >10,000 757 3.3 28.8 >10,000 758 5.0 34.7 >10,000 759 3.0 60.8 >10,000 760 6.0 25.4 >10,000 761 5.0 41.8 >10,000 769 5.0 0.7 >10,000 770 270 485 >10,000 771 500 10,000 >10,000 772 350 4200 >10,000 773 6.0 2.7 >10,000 774 — — — 775 120 270 >10,000 776 3.0 10.0 >10,000 777 2.5 6.5 >10,000 778 3.3 12 >10,000 779 40 210 >10,000 780 17.5 80 >10,000 781 800 5100 >10,000 782 21.1 100 >10,000 784 6.0 4500 >10,000 786 3.7 700 >10,000 787 1.2 175 >10,000 788 3.0 445 >10,000 789 12.2 3700 >10,000 790 4.5 700 >10,000 791 2.0 700 >10,000 793 4.0 23.5 >10,000 794 1500 2900 >10,000 796 5.7 130 >10,000 797 4.0 175 >10,000 798 20.0 210 >10,000 799 10.6 43.5 >10,000 802 2.3 10,000 >10,000 807 200 1400 >10,000 811 14.8 110 >10,000 815 140 1400 >10,000 816 1200 >10,000 >10,000 820 29.0 1400 >10,000 821 4.0 10.0 >10,000 822 10.0 210 >10,000 823 7.0 505 >10,000 825 11.3 70.0 >10,000 826 40.0 650 ND 827 10.0 540 >10,000 828 1.5 12.8 ND 829 6.0 22.0 ND 830 17.9 2100 >10,000 831 2.3 170 >10,000 832 18.1 2000 >10,000 833 11.0 1750 >10,000 834 150 780 ND 835 6.0 20.0 >10,000 836 135 4200 ND 838 3.0 70.0 >10,000 841 285 1900 ND 842 5.5 45.4 >10,000 844 5.0 4700 >10,000 845 28.6 2000 ND 846 4.5 186 >10,000 847 20.0 1800 ND 848 — — ND 850 4.5 150 >10,000 851 3.7 42.5 ND 852 25.0 3000 ND 853 15.8 120 ND 854 40.0 3300 ND 856 1.2 250 ND 857 1.3 120 ND 858 3.7 600 >10,000 859 5.5 440 ND 860 2.7 1500 >10,000 861 2.0 34.9 ND 862 1.7 40.0 ND 863 — — ND 864 — — ND 867 16.5 10,000 >10,000 868 — — ND 869 2.0 76.9 ND 870 305 6000 ND

Example 944 In Vivo Angiogenesis Assay

[0945] The study of angiogenesis depends on a reliable and reproducible model for the stimulation and inhibition of a neovascular response. The corneal micropocket assay provides such a model of angiogenesis in the cornea of a mouse. See, A Model of Angiogenesis in the Mouse Cornea; Kenyon, BM, et al., Investigative Ophthalmology & Visual Science, July 1996, Vol. 37, No. 8.

[0946] In this assay, uniformLy sized Hydron pellets containing bFGF and sucralfate were prepared and surgically implanted into the stroma mouse cornea adjacent to the temporal limbus. The pellets were formed by making a suspension of 20 μL sterile saline containing 10 μg recombinant bFGF, 10 mg of sucralfate and 10 μL of 12 percent Hydron in ethanol. The slurry was then deposited on a 10×10 mm piece of sterile nylon mesh. After drying, the nylon fibers of the mesh were separated to release the pellets.

[0947] The corneal pocket is made by anesthetizing a 7 week old C57B1/6 female mouse, then proptosing the eye with a jeweler's forceps. Using a dissecting microscope, a central, intrastromal linear keratotomy of approximately 0.6 mm in length is performed with a #15 surgical blade, parallel to the insertion of the lateral rectus muscle. Using a modified cataract knife, a lamellar micropocket is dissected toward the temporal limbus. The pocket is extended to within 1.0 mm of the temporal limbus. A single pellet was placed on the corneal surface at the base of the pocket with a jeweler's forceps. The pellet was then advanced to the temporal end of the pocket. Antibiotic ointment was then applied to the eye.

[0948] Mice were dosed on a daily basis for the duration of the assay. Dosing of the animals was based on bioavailability and overall potency of the compound. an exemplary dose was 10 or 50 mg/kg (mpk) bid, po. Neovascularization of the corneal stroma begins at about day three and was permitted to continue under the influence of the assayed compound until day five. At day five, the degree of angiogenic inhibition was scored by viewing the neovascular progression with a slit lamp microscope.

[0949] The mice were anesthetized and the studied eye was once again proptosed. The maximum vessel length of neovascularization, extending from the limbal vascular plexus toward the pellet was measured. In addition, the contiguous circumferential zone of neovascularization was measured as clock hours, where 30 degrees of arc equals one clock hour. The area of angiogenesis was calculated as follows. ${area} = \frac{\left( {0.4 \times {clock}\quad {hours} \times 3.14 \times {vessel}\quad {length}\quad \left( {{in}\quad {mm}} \right)} \right)}{2}$

[0950] Five to six mice were utilized for each compound in each study. The studied mice were thereafter compared to control mice and the difference in the area of neovascularization was recorded as an averaged value. Each group of mice so studied constitutes an “n” value of one, so that “n” values greater than one represent multiple studies whose averaged result is provided in the table. A contemplated compound typically exhibits about 25 to about 75 percent inhibition, whereas the vehicle control exhibits zero percent inhibition.

EXAMPLE 350 In Vivo PC-3 Tumor Reduction

[0951] PC-3 human pancreatic cancer eclls (ATCC CRL 1435) were grown to 90% confluence in F12/MEM (Gibco) containing 7% FBS (Gibco). Cells were mechanically harvested using a rubber scraper, and then washed twice with cold medium. The resulting cells were resuspended in cold medium with 30% matrigel (Collaborative Research) and the cell-containing medium was maintained on ice until used.

[0952] Balb/c nu/nu mice at 7-9 weeks of age were anesthetized with avertin [2,2,2-tribromethanol/t-amyl alcohol (1 g/l mL) diluted 1:60 into phosphate-buffered sline] and 3-5×10⁶ of the above cells in 0.2 mL of medium were injected into the left flank of each mouse. Cells were injected in the morning, whereas dosing with an inhibitor began at 6 PM. The animals were gavaged BID from day zero (cell injection day) to day 25-30, at which time the animals were euthanized and tumors weighed.

[0953] Compounds were dosed at 10 mg/mL in 0.5% methylcellulose/0.1% polysorbate 80 to provide a 50 mg/kg (mpk) dose twice each day, or diluted to provide a 10 mg/kg (mpk) dose twice each day. Tumor measurements began on day 7 and continued every third or fourth day until completion of the study. Groups of ten mice were used in each study and nine to ten survived. Each group of mice so studied constitutes an “n” value of one, so that “n” values greater than one represent multiple studies whose averaged result is provided in the table.

EXAMPLE 945 Tumor Necrosis Factor Assays

[0954] Cell Culture.

[0955] The cells used in the assay are the human moncytic line U-937 (ATCC CRL-1593). The cells are grown in RPMI w/10% FCS and PSG supplement (R-10) and are not permitted to overgrow. The assay is carried out as follows:

[0956] 1. Count, then harvest cells by centrifugation. Resuspend the pellet in R-10 supplement to a concentration of 1.540×10⁶ cells/mL.

[0957] 2. Add test compound in 65 μL R-10 to the appropriate wells of a 96-well flat bottom tissue culture plate. The initial dilution from a DMSO stock (0.100 mM compound) provides a 400 μM solution, from which five additional three-fold serial dilutions are made. Each dilution of 65 μl (in triplicate) yields final compound test concentrations of 100 μM, 33.3 μM, 11.1 μM, 3.7 μM, 1.2 μM and 0.4 μM.

[0958] 3. The counted, washed and resuspended cells (200,000 cells/well) in 130 μL are added to the wells.

[0959] 4. Incubation is for 45 minutes to one hour at 37° C. in 5% CO₂ in a water saturated container.

[0960] 5. R-10 (65 uL)containing 160 ng/mL PMA (Sigma) is added to each well.

[0961] 6. The test system is incubated at 37° C. in 5% CO₂ overnight (18-20 hours) under 100% humidity.

[0962] 7. Supernatant, 150 μL, is carefully removed from each well for use in the ELISA assay.

[0963] 8. For toxicity, a 50 μL aliquot of working solution containg 5 mL R-10, 5 mL MTS solution [CellTiter 96 AQueous One Solution Cell Proliferation Assay Cat.#G358/0,1 (Promega Biotech)] and 250 ul PMS solution are added to each well containing the remaining supernatant and cells and the cells incubated at 37° C. in 5% CO₂ until the color develops. The system is excited at 570 nm and read at 630 nm.

[0964] TNF Receptor II ELISA Assay

[0965] 1. Plate 100 μL/well 2 μg/mL mouse anti-human TNFrII antibody (R&D Systems #MAB226) in 1×PBS (pH 7.1, Gibco) on NUNC-Immuno Maxisorb plate. Incubate the plate at 4° C. overnight (about 18-20 hours).

[0966] 2. Wash the plate with PBS-Tween (1×PBS w/0.05% Tween).

[0967] 3. Add 200 μL 5% BSA in PBS and block at 37° C. in a water saturated atmosphere for 2 hours.

[0968] 4. Wash the plate with PBS-Tween.

[0969] 5. Add sample and controls (100 μl of each) to each well. The standards are 0, 50, 100, 200, 300 and 500 μg recombinant human TNFrII (R&D Systems #226-B2) in 100 μL 0.5% BSA in PBS. The assay is linear to between 400-500 pg of standard.

[0970] 6. Incubate at 37° C. in a saturated atmosphere for 1.5 hours.

[0971] 7. Wash the plate with PBS-Tween.

[0972] 8. Add 100 μL goat anti-human TNFrII polyclonal (1.5 μg/mL R&D Systems #AB226-PB in 0.5% BSA in PBS).

[0973] 9. Incubate at 37° C. in a saturated atmosphere for 1 hour.

[0974] 10. Wash the plate with PBS-Tween.

[0975] 11. Add 100 μL anti-goat IgG-peroxidase (1:50,000 in 0.5% BSA in PBS, Sigma #A5420). 

1-66. (canceled).
 67. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds in structure to the following formula:

R¹⁴ is selected from the group consisting of hydrogen and C(W)R²⁵; W is selected from the group consisting of O and S; R²⁵ is selected from the group consisting of C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, and amino C₁-C₆-alkyl, wherein: the amino C₁-C₆-alkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxycarbonyl, and C₁-C₆-alkanoyl, or the amino C₁-C₆-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring; g is zero, 1, or 2; m is zero, 1, or 2; n is zero, 1, or 2; p is zero, 1, or 2; the sum of m+n+p=1,2,3, or 4; as to X, Y, and Z: (a) one of X, Y, and Z is selected from the group consisting of C(O), S, S(O), S(O)₂, and NS(O)₂R⁷, and the remaining two of X, Y, and Z are CR⁸R⁹, and CR¹⁰R¹¹, or (b) X and Z, or Z and Y together constitute a moiety selected from the group consisting of NR⁶C(O), NR⁶S(O), NR⁶S(O)₂, NR⁶S, NR⁶⁰, SS, NR⁶NR⁶, and OC(O), with the remaining one of X and Y being CR⁸R⁹, or (c) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of:

wherein wavy lines are bonds to the atoms of the depicted ring; R⁶ and R⁶′ are independently selected from the group consisting of hydrogen, formyl, sulfonic-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkylcarbonyl, hydroxycarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C₁-C₆-alkylcarbonylcarbonyl, R⁸R⁹-aminocarbonylcarbonyl, C₁-C₆-alkanoyl, aryl-C₁-C₆-alkyl, aroyl, bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)-C₁-C₆-alkyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-perfluoroalkyl, C₁-C₆-trifluoromethylalkyl, C₁-C₆-perfluoroalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, arylsulfonyl, C₁-C₆-alkylsulfonyl, 5- to 6-membered heteroarylsulfonyl, carboxy-C₁-C₆-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl, aminocarbonyl, C₁-C₆-alkyl(R⁸N)iminocarbonyl, aryl(R⁸N)iminocarbonyl, 5- to 6-membered heterocyclo(R⁸N)iminocarbonyl, arylthio-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₃-C₆-alkenyl, C₁-C₄-alkylthio-C₃-C₆-alkenyl, 5- to 6-membered heteroaryl-C₁-C₆-alkyl, halo-C₁-C₆-alkanoyl, hydroxy-C₁-C₆-alkanoyl, thiol-C₁-C₆-alkanoyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkoxycarbonyl, aryloxycarbonyl, NR⁸R⁹—(R⁸)iminomethyl, NR⁸R⁹—C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, R⁸R⁹-aminocarbonyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkylcarbonyl, hydroxyaminocarbonyl, R⁸R⁹-aminosulfonyl, R⁸R⁹-aminosulfon-C₁-C₆-alkyl, R⁸R⁹-amino-C₁-C₆-alkylsulfonyl, and R⁸R⁹-amino-C₁-C₆-alkyl; R⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl, and C₁-C₆-hydroxyalkyl; as to R⁸: R⁸ is selected from the group consisting of hydrogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclo-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, arylalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl, arylsulfinyl-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, heteroarylsulfonyl-C₁-C₆-alkyl, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, and C₁-C₆-alkanoyl, or R⁸ and R⁹, together with the carbon to which they are bonded, form a carbonyl group, or R⁸ and R⁹ or R⁸ and R¹⁰, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R⁹: R⁹ is selected from the group consisting of hydrogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclo-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, arylalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl, arylsulfinyl-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, heteroarylsulfonyl-C₁-C₆-alkyl, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, and C₁-C₆-alkanoyl, or R⁸ and R⁹, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R¹⁰: R¹⁰ is selected from the group consisting of hydrogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclo-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, arylalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl, arylsulfinyl-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, heteroarylsulfonyl-C₁-C₆-alkyl, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, and C₁-C₆-alkanoyl, R¹⁰ and R¹¹, together with the carbon to which they are bonded, form a carbonyl group, or R¹⁰ and R¹¹ or R⁸ and R¹⁰, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R¹¹: R¹¹ is selected from the group consisting of hydrogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclo-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, arylalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl, arylsulfinyl-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, heteroarylsulfonyl-C₁-C₆-alkyl, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, and C₁-C₆-alkanoyl, or R¹⁰ and R¹¹, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; only one of R⁸ and R⁹ or R¹⁰ and R¹¹ is hydroxy; R¹² and R¹²′ are independently selected from the group consisting of hydrogen, C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroarylalkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclo-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl, arylsulfinyl-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, heteroarylsulfonyl-C₁-C₆-alkyl, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, and C₁-C₆-alkanoyl; R¹³ is selected from the group consisting of hydrogen, benzyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, and C₁-C₆-hydroxyalkyl; Q is a 5- to 7-membered heterocyclic ring (other than piperazinyl) containing one or two nitrogen atoms; A is selected from the group consisting of: (1)—O—, (2) —S—, (3) —NR¹⁷—, (4) —CO—N(R¹⁷), (5) —N(R¹⁷)—CO—, (6) —CO—O—, (7) —O—CO—, (8) —O—CO—O—, (9) —HC═CH—, (10) —NH—CO—NH—, (11) —C≡C—, (12)—NH—CO—O—, (13) —O—CO—NH—, (14) —N═N—, (15) —NH—NH—, (16) —CS—N(R¹⁷)—, (17) —N(R¹⁷)—CS—, and (18) a bond; R¹⁷ is selected from the group consisting of hydrogen, C₁-C₄-alkyl, and phenyl; R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocyclothioalkyl, wherein: the aryl, heteroaryl, cycloalkyl, or heterocyclo is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C₁-C₂-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; R is other than alkyl or alkoxyalkyl when A is —O— or —S—; E is selected from the group consisting of: (1) —CO(R¹⁹)—, (2) —(R¹⁹)CO—, (3) —CONH—, (4) —HNCO—, (5) —CO—, (6) —SO₂—R¹⁹—, (7) —R¹⁹—SO₂—, (8) —SO₂—, (9)—NH—SO₂—, (10) —SO₂—NH—, (11) —S—, (12) —NH—CO—O—, (13) —O—CO—NH—, and (14) a bond; R¹⁹ is selected from the group consisting of heterocycloalkyl and cycloalkyl; and Y² is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
 68. A compound or salt according to claim 67, wherein g is
 2. 69. A compound or salt according to claim 68, wherein A-R-E-Y² is bonded at the 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 6- or 7-membered ring, and at the 3- or 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 5-membered ring.
 70. A compound or salt according to claim 69, wherein R¹⁴ is hydrogen.
 71. A compound or salt according to claim 69, wherein: R¹⁴ is C(W)R²⁵; W is O; and R²⁵ is selected from the group consisting of C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, and aryloxy.
 72. A compound or salt according to claim 69, wherein A is selected from the group consisting of —O— and —S—.
 73. A compound or salt according to claim 69, wherein R is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclo.
 74. A compound or salt according to claim 69, wherein the compound corresponds in structure to formula B-1A:


75. A compound or salt according to claim 69, wherein Q is a 5-membered ring.
 76. A compound or salt according to claim 69, wherein Q is a 7-membered ring.
 77. A compound or salt according to claim 69, wherein Q is a 6-membered ring.
 78. A compound or salt according to claim 77, wherein the compound corresponds in structure to the following formula:


79. A compound or salt according to claim 78, wherein: the compound corresponds in structure to the following formula:

Z is selected from the group consisting of C(O), S, S(O), S(O)₂, and NS(O)₂R⁷.
 80. A compound or salt according to claim 79, wherein R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, and cycloalkylthioalkyl, wherein: the aryl, heteroaryl, or cycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C₁-C₂-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl.
 81. A compound or salt according to claim 80, wherein R is selected from the group consisting of aryl, heteroaryl, and cycloalkyl.
 82. A compound or salt according to claim 79, wherein Z is S.
 83. A compound or salt according to claim 68, wherein the compound corresponds in structure to the formula:


84. A compound or salt according to claim 83, wherein R-E-Y² is bonded at the 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 6- or 7-membered ring, and at the 3- or 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 5-membered ring.
 85. A compound or salt according to claim 84, wherein: the compound corresponds in structure to formula XI-1:

Z is selected from the group consisting of C(O), S, S(O), S(O)₂, and NS(O)₂R⁷.
 86. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound corresponds in structure to the following formula:

R¹⁴ is selected from the group consisting of hydrogen and C(W)R²⁵; W is selected from the group consisting of O and S; R²⁵ is selected from the group consisting of C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, and amino C₁-C₆-alkyl, wherein: the amino C₁-C₆-alkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxycarbonyl, and C₁-C₆-alkanoyl, or the amino C₁-C₆-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring; g is zero, 1, or 2; m is zero, 1, or 2; n is zero, 1, or 2; p is zero, 1, or 2; the sum of m+n+p=1, 2, 3, or 4; as to X, Y, and Z: (a) one of X, Y, and Z is selected from the group consisting of C(O), S, S(O), S(O)₂, and NS(O)₂R⁷, and the remaining two of X, Y, and Z are CR⁸R⁹, and CR¹⁰R¹¹, or (b) X and Z, or Z and Y together constitute a moiety selected from the group consisting of NR⁶C(O), NR⁶S(O), NR⁶S(O)₂, NR⁶S, NR⁶⁰, SS, NR⁶NR⁶, and OC(O), with the remaining one of X and Y being CR⁸R⁹, or (c) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of:

wherein wavy lines are bonds to the atoms of the depicted ring; R⁶ and R⁶ are independently selected from the group consisting of hydrogen, formyl, sulfonic-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkylcarbonyl, hydroxycarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylcarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C₁-C₆-alkylcarbonylcarbonyl, R⁸R⁹-aminocarbonylcarbonyl, C₁-C₆-alkanoyl, aryl-C₁-C₆-alkyl, aroyl, bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)-C₁-C₆-alkyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-perfluoroalkyl, C₁-C₆-trifluoromethylalkyl, C₁-C₆-perfluoroalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, arylsulfonyl, C₁-C₆-alkylsulfonyl, 5- to 6-membered heteroarylsulfonyl, carboxy-C₁-C₆-alkyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl, aminocarbonyl, C₁-C₆-alkyl(R⁸N)iminocarbonyl, aryl(R⁸N)iminocarbonyl, 5- to 6-membered heterocyclo(R⁸N)iminocarbonyl, arylthio-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₃-C₆-alkenyl, C₁-C₄-alkylthio-C₃-C₆-alkenyl, 5- to 6-membered heteroaryl-C₁-C₆-alkyl, halo-C₁-C₆-alkanoyl, hydroxy-C₁-C₆-alkanoyl, thiol-C₁-C₆-alkanoyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₅-alkoxycarbonyl, aryloxycarbonyl, NR⁸R⁹—(R⁸)iminomethyl, NR⁸R⁹—C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, R⁸R⁹-aminocarbonyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkylcarbonyl, hydroxyaminocarbonyl, R⁸R⁹-aminosulfonyl, R⁸R⁹-aminosulfon-C₁-C₆-alkyl, R⁸R⁹-amino-C₁-C₆-alkylsulfonyl, and R⁸R⁹-amino-C₁-C₆-alkyl; R⁷ is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl, C₁-C₆-carboxyalkyl, and C₁-C₆-hydroxyalkyl; as to R⁸: R⁸ is selected from the group consisting of hydrogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclo-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, arylalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl, arylsulfinyl-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, heteroarylsulfonyl-C₁-C₆-alkyl, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, and C₁-C₆-alkanoyl, or R⁸ and R⁹, together with the carbon to which they are bonded, form a carbonyl group, or R⁸ and R⁹ or R⁸ and R¹⁰, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R⁹: R⁹ is selected from the group consisting of hydrogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol -C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclo-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, arylalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl, arylsulfinyl-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, heteroarylsulfonyl-C₁-C₆-alkyl, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, and C₁-C₆-alkanoyl, or R⁸ and R⁹, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R¹⁰: R¹⁰ is selected from the group consisting of hydrogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclo-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, arylalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl, arylsulfinyl-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, heteroarylsulfonyl-C₁-C₆-alkyl, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, and C₁-C₆-alkanoyl, R¹⁰ and R¹¹, together with the carbon to which they are bonded, form a carbonyl group, or R¹⁰ and R¹¹ or R⁸ and R¹⁰, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R¹¹: R¹¹ is selected from the group consisting of hydrogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkanoyl, aroyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclo-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, arylalkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl, arylsulfinyl-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, heteroarylsulfonyl-C₁-C₆-alkyl, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, and C₁-C₆-alkanoyl, or R¹⁰ and R¹¹, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; only one of R⁸ and R⁹ or R¹⁰ and R¹¹ is hydroxy; R¹² and R¹² are independently selected from the group consisting of hydrogen, C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl, heteroaryl, heteroarylalkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclo-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, amino-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, hydroxycarbonyl-C₁-C₆-alkyl, hydroxycarbonylaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl, aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl, arylsulfinyl-C₁-C₆-alkyl, heteroarylsulfinyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, arylsulfonyl-C₁-C₆-alkyl, heteroarylsulfonyl-C₁-C₆-alkyl, perfluoro-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, and C₁-C₆-alkanoyl; R¹³ is selected from the group consisting of hydrogen, benzyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, and C₁-C₆-hydroxyalkyl; Q is a 5- to 7-membered heterocyclic ring (other than piperazinyl) containing one or two nitrogen atoms; E is selected from the group consisting of: (1) —CO(R¹⁹)—, (2) —(R¹⁹)CO—, (3) —CONH—, (4) —HNCO—, (5) —CO—, (6) —SO₂—R¹⁹—, (7) —R¹⁹—SO₂—, (8) —SO₂—, (9) —NH—SO₂—, (10) —SO₂—NH—, (11) —S—, (12) —NH—CO—O—, (13) —O—CO—NH—, and (14) a bond; R¹⁹ is selected from the group consisting of heterocycloalkyl and cycloalkyl; and Y² is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocyclo, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, aralkyl, heterocyclo, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
 87. A compound or salt according to claim 86, wherein g is
 2. 88. A compound or salt according to claim 87, wherein the compound corresponds in structure to the following formula:


89. A compound or salt according to claim 87, wherein: the compound corresponds in structure to formula IX-2:

Z is selected from the group consisting of C(O), S, S(O), S(O)₂, and NS(O)₂R⁷.
 90. A compound or salt according to claim 87, wherein E-Y² is bonded at the 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 6- or 7-membered ring, and at the 3- or 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 5-membered ring.
 91. A compound or salt according to claim 90, wherein Y² is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
 92. A compound or salt according to claim 90, wherein R¹⁴ is hydrogen.
 93. A compound or salt according to claim 90, wherein: R¹⁴ is C(W)R²⁵; W is O; and R²⁵ is selected from the group consisting of C₁-C₆-alkyl, aryl, C₁-C₆-alkoxy, heteroaryl-C₁-C₆-alkyl, C₃-Cs-cycloalkyl-C₁-C₆-alkyl, and aryloxy.
 94. A compound or salt according to claim 90, wherein the compound corresponds in structure to formula B-3A:


95. A compound or salt according to claim 90, wherein Q is a 5-membered ring.
 96. A compound or salt according to claim 90, wherein Q is a 7-membered ring.
 97. A compound or salt according to claim 90, wherein Q is a 6-membered ring.
 98. A compound or salt according to claim 97, wherein the compound corresponds in structure to the following formula:


99. A compound or salt according to claim 98, wherein: the compound corresponds in structure to formula IX-1:

Z is selected from the group consisting of C(O), S, S(O), S(O)₂, and NS(O)₂R⁷.
 100. A compound or salt according to claim 99, wherein Y² is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
 101. A compound or salt according to claim 99, wherein Z is S.
 102. A compound or salt according to claim 101, wherein the compound corresponds in structure to the formula:


103. A method for treating a pathological condition in a mammal, wherein: the condition is treatable by inhibiting matrix metalloprotease activity; the method comprises administering a compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is effective to treat the condition; the compound corresponds in structure to a compound recited in claim 68; and the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1.
 104. A method according to claim 103, wherein A is a bond.
 105. A method according to claim 103, wherein the pathological condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's disease, coronary thrombosis, and bone disease.
 106. A method according to claim 105, wherein the pathological condition is osteoarthritis.
 107. A method according to claim 103, wherein the compound or salt is administered a plurality of times.
 108. A method for treating a pathological condition in a mammal, wherein: the condition is treatable by inhibiting matrix metalloprotease activity; the method comprises administering a compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is effective to treat the condition; the compound corresponds in structure to a compound recited in claim 87; and the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1.
 109. A method according to claim 108, wherein the pathological condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's disease, coronary thrombosis, and bone disease.
 110. A method according to claim 109, wherein the pathological condition is osteoarthritis.
 111. A method according to claim 108, wherein the compound or salt is administered a plurality of times.
 112. A pharmaceutical composition that comprises a compound or salt according to claim 68 dissolved or dispersed in a pharmaceutically acceptable carrier.
 113. A pharmaceutical composition according to claim 112, wherein A is a bond.
 114. A pharmaceutical composition that comprises a compound or salt according to claim 87 dissolved or dispersed in a pharmaceutically acceptable carrier. 